JP6521387B2 - Fused heterocyclic compound - Google Patents

Description

  The present invention relates to a novel compound having an inhibitory action on cyclin dependent kinase 8 (cyclin-dependent kinase (hereinafter sometimes abbreviated as CDK) 8) and / or CDK19 or a salt thereof. Furthermore, the present invention relates to a medicament for preventing or treating CDK8- and / or CDK19-related diseases including cancer and the like, comprising the compound or a salt thereof.

BACKGROUND OF THE INVENTION
Cyclin dependent kinases (CDKs) are phosphorylation enzymes that are activated in complex with cyclin proteins and have been discovered as factors regulating the cell cycle. In humans, at least 21 types of CDK (CDK1-10, 11A, 11B, 12-20) are known.
Human CDK8 (GenBank Accession No .: NM_001260) is found as an enzyme that forms a complex with cyclin C to phosphorylate RNA polymerase C-terminal domain etc and is considered to be a factor involved in transcription regulation . Human CDK19 (GenBank Accession No .: NM_015076) is a protein having an amino acid sequence having about 80% identity with human CDK8.

  Patent Document 1 suggests that CDK8 and / or CDK19 inhibitory compounds may be useful for the treatment or prevention of cancer.

  Patent Document 2 discloses fused thiophene derivative compounds useful for suppressing bone diseases, osteosarcoma and the like.

US Patent Publication US 2012/0071477 International Publication WO 2001/074823 Brochure

  An object of the present invention is to provide a compound which has excellent CDK8 and / or CDK19 inhibitory activity and is sufficiently satisfactory as a pharmaceutical.

  When the present inventors intensively studied in view of the above background, they found that the compounds represented by the following formulas have an activity of inhibiting CDK8 and / or CDK19, and came to complete the present invention. That is, the present invention is as follows.

[1] Formula:

[In the formula,
R ¹ represents a substituent;
R ² represents a substituent or a hydrogen atom;
R ^3a and R ^4a independently represent a hydrogen atom or a substituent;
R ^3b and R ^4b independently represent a hydrogen atom or a substituent, or are taken together (i) to form a double bond, or (ii) substituted together with the carbon atom to which they are attached _Optionally form _C3-4 cycloalkyl;
X represents CR ⁵ or N;
R ⁵ represents a hydrogen atom or a substituent;
L represents a spacer or a bond. ]
Or a salt thereof (which may be abbreviated as “compound (I)” in the present specification).
[2] The compound of the above-mentioned [1] or a salt thereof, wherein R ¹ is a carbamoyl group.
[3] R ² is
(I) (1) halogen atom,
(2) cyano group,
(3) C _1-6 alkyl group,
(4) (a) hydroxy group, and
(B) _C1-6 alkoxy group
May be substituted by 1 to 3 substituents selected from
The alkyl may be mono- or di-substituted with a C _1-6 alkyl group
Lvamoyl group,
(5) C _3-10 cycloalkyl-carbamoyl group,
(6) carboxy group,
(7) C _1-6 alkoxy-carbonyl group,
(8) (a) hydroxy group, and
(B) _C1-6 alkoxy group
May be substituted by 1 to 5 substituents selected from
3- to 14-membered non-aromatic heterocyclic carbonyl group,
(9) carbamimidoyl group, and (10) _{(i) C 1-6} alkyl group,
(Ii) (a) hydroxy group, and
(B) _C1-6 alkoxy group
Substituted with 1 to 3 substituents selected from
_Optionally substituted C _1-6 alkyl-carbonyl group,
(Iii) may be substituted by 1 to 3 hydroxy groups
C _3-10 cycloalkyl-carbonyl group,
(Iv) C _1-6 alkoxy-carbonyl group, and
(V) substituted with 1 to 3 C _1-6 alkyl groups
Good oxetanyl-carbonyl group
May be mono- or di-substituted with a substituent selected from
Amino group
5 optionally substituted by 1 to 3 substituents selected from
To 6-membered nitrogen-containing aromatic heterocyclic groups;
(II) (1) halogen atom,
(2) cyano group,
(3) It may be substituted by 1 to 3 halogen atoms
C _1-6 alkyl group,
(4) 1 to 3 3- to 14-membered non-aromatic heterocycle-carbonyl
Group,
(5) It may be substituted by 1 to 3 C _1-6 alkoxy groups
The alkyl may be mono- or di-substituted with a C _1-6 alkyl group
Lvamoyl group,
(6) C _1-6 alkyl - sulfonyl group, and (7) optionally substituted 1 to 5 halogen atoms Sulf
C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from phenyl group; or (III) C optionally substituted by 1 to 3 C _1-6 alkoxy group The compound or its salt of the said [1] or [2] description which is a _1-6 alkyl group.
[4] The compound or the salt thereof according to any of the above-mentioned [1] to [3], wherein R ^3a , R ^4a , R ^3b and R ^4b are all hydrogen atoms.
[5] The compound or a salt thereof according to any of the above-mentioned [1] to [4], wherein X is CH.
[6] The compound or a salt thereof according to any of the above-mentioned [1] to [5], wherein L is -O-.
[7] R ¹ is
(1) (i) hydroxy group,
(Ii) (a) hydroxy group,
(B) C _1-6 alkoxy group,
(C) cyano group,
(D) optionally halogenated C _3-10 cycloalkyl group,
(E) 5- to 6-membered monocyclic aromatic heterocyclic group,
(F) 3- to 8-membered monocyclic non-aromatic heterocyclic group, and
_{(G) (A) C 1-6} alkyl group, and
_{(B) C 1-6} alkyl - group
Even if it is mono- or di-substituted by a substituent selected from
Good amino group
May be substituted by 1 to 3 substituents selected from
C _1-6 alkyl group,
(Iii) C _1-6 alkoxy group,
(Iv) optionally halogenated C _3-10 cycloalkyl group,
(V) a C _6-14 aryl group _optionally having 1 to 7 halogen atoms,
(Vi) a 5- to 6-membered monocyclic aromatic heterocyclic group which may be substituted by 1 to 3 C _1-6 alkyl groups,
(Vii) 3- to 8-membered monocyclic non-aromatic heterocyclic group,
(Viii) a carbamoyl group which may be mono- or di-substituted with a substituent selected from (7) a C _7-16 aralkyl group, and (ix) a C _7-16 aralkyloxy group,
(2) C _1-6 alkyl-carbonyl group,
(3) carboxy group,
(4) a C _1-6 alkoxy-carbonyl group, or (5) a cyano group;
R ² is
(I) (1) halogen atom,
(2) cyano group,
(3) C _1-6 alkyl group,
(4) (a) hydroxy group, and
(B) _C1-6 alkoxy group
May be substituted by 1 to 3 substituents selected from
The alkyl may be mono- or di-substituted with a C _1-6 alkyl group
Lvamoyl group,
(5) C _3-10 cycloalkyl-carbamoyl group,
(6) carboxy group,
(7) C _1-6 alkoxy-carbonyl group,
(8) (a) hydroxy group, and
(B) _C1-6 alkoxy group
3 optionally substituted by 1 to 5 substituents selected from
To 14-membered non-aromatic heterocyclic carbonyl group,
(9) carbamimidoyl group, and (10) _{(i) C 1-6} alkyl group,
(Ii) (a) hydroxy group, and
(B) _C1-6 alkoxy group
Substituted with 1 to 3 substituents selected from
Optionally C _1-6 alkyl-carbonyl group,
(Iii) may be substituted by 1 to 3 hydroxy groups
C _3-10 cycloalkyl-carbonyl group,
(Iv) C _1-6 alkoxy-carbonyl group, and
(V) Even if substituted by 1 to 3 C _1-6 alkyl groups
Good oxetanyl-carbonyl group
May be mono- or di-substituted with a substituent selected from
A 5- or 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from amino groups;
(II) (1) halogen atom,
(2) cyano group,
(3) It may be substituted by 1 to 3 halogen atoms
C _1-6 alkyl group,
(4) 3- to 14-membered non-aromatic heterocycle-carbonyl group,
(5) It may be substituted by 1 to 3 C _1-6 alkoxy groups
It may be mono- or di-substituted with a C _1-6 alkyl group
A carbamoyl group,
(6) C _1-6 alkyl - sulfonyl group, and (7) optionally substituted 1 to 5 halogen atoms Sulf
C _6-14 aryl group optionally substituted by 1 to 3 substituents selected from phenyl group; or (III) C optionally substituted by 1 to 3 C _1-6 alkoxy group _1-6 alkyl group;
R ^3a is a hydrogen atom or a C _1-6 alkyl group;
R ^4a is a hydrogen atom;
R ^3b is a hydrogen atom or a C _1-6 alkyl group, and R ^4b is a hydrogen atom, or R ^3b and R ^4b together form a double bond;
X is N or CH;
The compound of the above-mentioned [1] or a salt thereof, wherein L is -O-, -S-, -SO-, -SO ₂ -or a bond.
[8] 8-((2-Methyl-1-oxidopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide, or a salt thereof .
[9] 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide Or its salt.
[10] 8-((6-((2-hydroxy-2-methylpropyl) carbamoyl) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,1 2] Benzothiazole-6-carboxamide, or a salt thereof.
[11] 8-((6-((Cyclopropylcarbonyl) amino) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole 6-carboxamide or a salt thereof.
[12] 8-((1,3,5-Trimethyl-1H-pyrazol-4-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide, Or its salt.
[13] A medicament comprising the compound according to any one of the above [1] to [12] or a salt thereof.
[14] The medicine according to the above-mentioned [13], which is an inhibitor of CDK8 and / or CDK19.
[15] The medicine according to the above-mentioned [13] or [14], which is an agent for the prophylaxis or treatment of cancer.
[16] A method of inhibiting CDK8 and / or CDK19 in a mammal, comprising administering an effective amount of the compound or the salt thereof described in any of the above-mentioned [1] to [12] to the mammal .
[17] A method for the prophylaxis or treatment of cancer in a mammal, which comprises administering an effective amount of the compound or the salt thereof described in any of the above-mentioned [1] to [12] to the mammal.
[18] The compound according to any one of the above-mentioned [1] to [12] or a salt thereof for use in the prophylaxis or treatment of cancer.
[19] Use of the compound of any of the above-mentioned [1] to [12] or a salt thereof for the production of a preventive / therapeutic agent for cancer.

  The compounds or medicaments of the present invention have excellent inhibitory activity on CDK8 and / or CDK19 enzyme activity. Therefore, the compound or medicament of the present invention can be used as a CDK8 and / or CDK19 inhibitor, and is useful as a prophylactic or therapeutic agent for diseases that may be affected by CDK8 and / or CDK19, such as cancer, is there.

(Detailed Description of the Invention)
Hereinafter, the compounds of the present invention, their production methods and uses will be described in detail.

Hereinafter, the definition of each substituent used in the present specification will be described in detail. Each substituent has the following definition, unless otherwise stated.
In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.
In the present specification, examples of the "C _1-6 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl.
In the present specification, the "optionally halogenated C _1-6 alkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 An alkyl group is mentioned. Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl and 2,2- Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri And fluoropentyl, hexyl and 6,6, 6-trifluorohexyl.
In the present specification, examples of the " _C2-6 alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Examples include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
In the present specification, examples of the " _C2-6 alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- And pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl.
In the present specification, examples of the "C _3-10 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, adamantyl.
In the present specification, the "optionally halogenated C _3-10 also be cycloalkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _{3- And 10} cycloalkyl groups. Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In the present specification, examples of the "C _3-10 cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
In the present specification, examples of the "C _6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.
In the present specification, examples of the "C _7-16 aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C _1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
In the present specification, the "optionally halogenated C _1-6 alkoxy group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 An alkoxy group is mentioned. Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyl And oxy and hexyloxy.
In the present specification, examples of the "C _3-10 cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
In the present specification, examples of the "C _1-6 alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
In the present specification, the "optionally halogenated C _1-6 alkylthio group optionally", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C _1-6 An alkylthio group is mentioned. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.
In the present specification, examples of the “C _1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2, 2- Dimethylpropanoyl, hexanoyl, heptanoyl can be mentioned.
In the present specification, examples of the “ _optionally halogenated C _1-6 alkyl-carbonyl group” include, for example, C ₁ optionally having 1 to 7, preferably 1 to 5 halogen atoms. _{And -6} alkyl-carbonyl group. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
In the present specification, as the "C _1-6 alkoxy-carbonyl group", for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, And pentyloxycarbonyl and hexyloxycarbonyl.
In the present specification, examples of the "C _6-14 aryl-carbonyl group" include benzoyl, 1-naphthoyl and 2-naphthoyl.
In the present specification, examples of the "C _7-16 aralkyl-carbonyl group" include phenylacetyl and phenylpropionyl.
In the present specification, examples of the "5- to 14-membered aromatic heterocyclic carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclic carbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C _1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl.
In the present specification, examples of the "mono- or di-C _7-16 aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl.
In the present specification, examples of the "C _1-6 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
In the present specification, the “optionally halogenated C _1-6 alkylsulfonyl group” is, for example, C _1-, which may have 1 to 7, preferably 1 to 5 halogen atoms. ₆ alkyl sulfonyl group is mentioned. Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.
In the present specification, examples of the "C _6-14 arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and the like. Amino group, carbamoyl group which may be substituted, thiocarbamoyl group which may be substituted, sulfamoyl group which may be substituted, hydroxy group which may be substituted, sulfanyl which may be substituted And SH) groups and silyl groups which may be substituted.
In the present specification, examples of the “hydrocarbon group” (including the “hydrocarbon group” in the “optionally substituted hydrocarbon group”) include, for example, a C _1-6 alkyl group, a C _2-6 alkenyl group, A _C2-6 alkynyl group, a _C3-10 cycloalkyl group, a _C3-10 cycloalkenyl group, a _C6-14 aryl group, a _C7-16 aralkyl group is mentioned.

In the present specification, examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group which may have a substituent selected from the following Substituent Group A.
[Substituent group A]
(1) halogen atom,
(2) nitro group,
(3) cyano group,
(4) oxo group,
(5) hydroxy group,
(6) C _1-6 alkoxy group which may be halogenated,
(7) C _6-14 aryloxy group (eg, phenoxy, naphthoxy),
(8) C _7-16 aralkyloxy group (eg, benzyloxy),
(9) 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy),
(10) 3- to 14-membered non-aromatic heterocyclic oxy group (eg, morpholinyloxy, piperidinyloxy),
(11) C _1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy),
(12) C _6-14 aryl-carbonyloxy group (eg, benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),
(13) C _1-6 alkoxy-carbonyloxy group (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy)
(14) Mono- or di-C _1-6 alkyl-carbamoyloxy group (eg, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),
(15) C _6-14 aryl-carbamoyloxy group (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy),
(16) 5- to 14-membered aromatic heterocyclic carbonyloxy group (eg, nicotinoyl oxy),
(17) 3- to 14-membered non-aromatic heterocyclic carbonyloxy group (eg, morpholinyl carbonyloxy, piperidinyl carbonyloxy),
(18) C _1-6 alkylsulfonyloxy group which may be halogenated (eg, methylsulfonyloxy, trifluoromethylsulfonyloxy),
(19) a C _6-14 arylsulfonyloxy group which may be substituted by a C _1-6 alkyl group (eg, phenylsulfonyloxy, toluenesulfonyloxy),
(20) C _1-6 alkylthio group which may be halogenated,
(21) 5- to 14-membered aromatic heterocyclic group,
(22) 3- to 14-membered non-aromatic heterocyclic group,
(23) formyl group,
(24) carboxy group,
(25) C _1-6 alkyl-carbonyl group which may be halogenated,
(26) C _6-14 aryl-carbonyl group,
(27) 5- to 14-membered aromatic heterocyclic carbonyl group,
(28) 3- to 14-membered non-aromatic heterocyclic carbonyl group,
(29) C _1-6 alkoxy-carbonyl group,
(30) C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),
(31) C _7-16 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, phenethyloxycarbonyl),
(32) carbamoyl group,
(33) thiocarbamoyl group,
(34) mono- or di-C _1-6 alkyl-carbamoyl group,
(35) C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl),
(36) 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl, thienylcarbamoyl),
(37) 3- to 14-membered non-aromatic heterocyclic carbamoyl group (eg morpholinyl carbamoyl, piperidinyl carbamoyl),
(38) C _1-6 alkylsulfonyl group which may be halogenated,
(39) C _6-14 arylsulfonyl group,
(40) 5- to 14-membered aromatic heterocyclic sulfonyl group (eg, pyridylsulfonyl, thienylsulfonyl),
(41) optionally halogenated C _1-6 alkylsulfinyl group,
(42) C _6-14 arylsulfinyl group (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),
(43) 5- to 14-membered aromatic heterocyclic sulfinyl group (eg, pyridylsulfinyl, thienylsulfinyl),
(44) amino group,
(45) Mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N -Methylamino),
(46) mono- or di-C _6-14 arylamino group (eg, phenylamino),
(47) 5- to 14-membered aromatic heterocyclic amino group (eg, pyridylamino),
(48) C _7-16 aralkylamino group (eg, benzylamino),
(49) formylamino group,
(50) C _1-6 alkyl-carbonylamino group (eg, acetylamino, propanoylamino, butanoylamino),
(51) (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino group (eg, N-acetyl-N-methylamino),
(52) C _6-14 aryl-carbonylamino group (eg, phenylcarbonylamino, naphthylcarbonylamino),
(53) C _1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),
(54) C _7-16 aralkyloxy-carbonylamino group (eg, benzyloxycarbonylamino),
(55) C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino),
(56) a C _6-14 arylsulfonylamino group which may be substituted by a C _1-6 alkyl group (eg, phenylsulfonylamino, toluenesulfonylamino),
(57) C _1-6 alkyl group which may be halogenated,
(58) C _2-6 alkenyl group,
(59) C _2-6 alkynyl group,
(60) C _3-10 cycloalkyl group,
(61) _C3-10 cycloalkenyl group, and (62) _C6-14 aryl group.

The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
In the present specification, examples of the “heterocyclic group” (including the “heterocyclic group” in the “optionally substituted heterocyclic group”) include, for example, a nitrogen atom, a sulfur atom and a carbon atom as a ring constituting atom (I) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups and (iii) 7 to 10-membered hetero bridged ring groups, each containing 1 to 4 heteroatoms selected from oxygen atoms .

In the present specification, examples of the "aromatic heterocyclic group" (including the "5- to 14-membered aromatic heterocyclic group") include, as ring-constituting atoms, selected from nitrogen atoms, sulfur atoms and oxygen atoms in addition to carbon atoms. And 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing 1 to 4 heteroatoms.
Preferable examples of the “aromatic heterocyclic group” include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, , 5 to 6-membered monocyclic aromatic heterocyclic groups such as 3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl;
Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolo Pyridinyl, thiazolo pyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, flopirimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2,3 -B] thienyl, phenoxatyinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quina 8- to 14-membered fused polycyclic (preferably 2- or 3-ring) aromatic heterocyclic groups such as linyl, cinnolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like .

In the present specification, examples of the “non-aromatic heterocyclic group” (including “3- to 14-membered non-aromatic heterocyclic group”) include, as ring-constituting atoms, a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms. And 3 to 14-membered (preferably 4 to 10-membered) non-aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from
Preferred examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, and the like. Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl Tetrahydropyranyl tetrahydrothiopyranyl morpholinyl thiomorpholinyl azepanyl diaze Cycloalkenyl, azepinyl, oxepanyl, azocanyl, 3 to 8-membered monocyclic non-aromatic heterocyclic group such as Jiazokaniru;
Dihydrobenzofuranyl, dihydrobenzoimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisothiazolyl, dihydronaphtho [2,3-b] thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, Indolinyl, Isoindolinyl, Tetrahydrothieno [2,3-c] pyridinyl, Tetrahydrobenzoazepinyl, Tetrahydroquinoxalinyl, Tetrahydrophenanthridinyl, Hexahydrophenothiazinyl, Hexahydrophenoxazinyl, Tetrahydrophthalazinyl, Tetrahydrol Naphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydric acid Rofenajiniru, tetrahydrothiophenyl key Sante alkenyl, 9 to 14 membered fused polycyclic, such as octahydro-isoquinolylmethyl (preferably 2 or tricyclic), and the non-aromatic heterocyclic group.

In the present specification, preferable examples of the “7 to 10-membered hetero bridged ring group” include quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl.
In the present specification, as the "nitrogen-containing heterocyclic group", among the "heterocyclic groups", those containing at least one or more nitrogen atoms as ring-constituting atoms can be mentioned.
In the present specification, examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the above-mentioned substituent group A.
The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.

In the present specification, as the “acyl group”, for example, “1 selected from“ halogen atom, optionally halogenated C _1-6 alkoxy group, hydroxy group, nitro group, cyano group, amino group and carbamoyl group ” to three of the substituents may be _{respectively, C 1-6} alkyl _{groups, C 2-6} alkenyl _{groups, C 3-10 cycloalkyl, C 3-10} cycloalkenyl _{group, C 6-14} aryl Formyl optionally having one or two substituents each selected from a group, a C _7-16 aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group Groups, carboxy group, carbamoyl group, thiocarbamoyl group, sulfino group, sulfo group, sulfamoyl group and phosphono group.
In addition, as the “acyl group”, a hydrocarbon-sulfonyl group, a heterocycle-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocycle-sulfinyl group can also be mentioned.
Here, the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded, the heterocyclic ring-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded, and the hydrocarbon-sulfinyl group is a hydrocarbon group And a heterocycle-sulfinyl group mean a sulfinyl group to which a heterocyclic group is linked.
Preferable examples of the “acyl group” include a formyl group, a carboxy group, a C _1-6 alkyl-carbonyl group, a C _2-6 alkenyl-carbonyl group (eg, crotonoyl), a C _3-10 cycloalkyl-carbonyl group ( Examples: cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C _3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexene carbonyl), C _6-14 aryl-carbonyl group, C _7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl) , _{naphthyloxycarbonyl), C 7- 6} aralkyloxy - carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl carbonyl), a carbamoyl group, mono- - or di _{-C 1-6} alkyl - carbamoyl group, mono- - or di _{-C 2-6} alkenyl - carbamoyl group (e.g. , Diallylcarbamoyl), mono- or di-C _3-10 cycloalkyl-carbamoyl group (eg cyclopropylcarbamoyl), mono- or di-C _6-14 aryl-carbamoyl group (eg phenylcarbamoyl), mono- or Di-C _7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C _1-6 alkyl-thiocarbamoyl group (eg, methylthio) Carbamoyl, N-ethyl-N-methyl Okarubamoiru), mono - or di _{-C 2-6} alkenyl - thiocarbamoyl group (e.g., diallyl thio carbamoyl), mono - or di _{-C 3-10} cycloalkyl - thiocarbamoyl group (e.g., cyclopropyl thiocarbamoyl, cyclohexyl Thiocarbamoyl), mono- or di-C _6-14 aryl-thiocarbamoyl group (eg, phenylthiocarbamoyl), mono- or di-C _7-16 aralkyl-thiocarbamoyl group (eg, benzylthiocarbamoyl, phenethylthiocarbamoyl) ), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (eg, pyridylthiocarbamoyl), sulfino group, C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl), sulfo group, C _1-6 alkylsulfonyl _{group, C 6- 4} arylsulfonyl group, a phosphono group, a mono - or di -C _1-6 alkyl phosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) and the like.

In the present specification, the “optionally substituted amino group” is, for example, a C _1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group A, respectively, C _2-6 alkenyl _{group, C 3-10 cycloalkyl, C 6-14} aryl _{group, C 7-16 aralkyl, C 1-6} alkyl - carbonyl _{group, C 6-14} aryl - carbonyl _{group, C 7- 16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group , Mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _7-16 aralkyl-carbamoyl group, C _1-6 alkylsulfonyl group and C _6-1 Examples include an amino group which may have one or two substituents selected from ₄ arylsulfonyl groups.
Preferred examples of the amino group which may be substituted include amino group, mono- or di- (optionally halogenated C _1-6 alkyl) amino group (eg, methylamino, trifluoromethylamino, Dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C _2-6 alkenylamino group (eg, diallylamino), mono- or di-C _3-10 cycloalkylamino group (eg, Cyclopropylamino, cyclohexylamino), mono- or di-C _6-14 arylamino (eg, phenylamino), mono- or di-C _7-16 aralkylamino (eg, benzylamino, dibenzylamino), mono - or di - (optionally halogenated C _1-6 alkyl) - carbonyl amino group (e.g., a Chiruamino, propionylamino), mono- - or di _{-C 6-14} aryl - carbonyl amino group (e.g., benzoylamino), mono - or di _{-C 7-16} aralkyl - carbonyl amino group (e.g., benzyl carbonyl amino), mono -Or di-5- to 14-membered aromatic heterocyclic carbonylamino group (eg, nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclic carbonylamino group (eg, piperidine) N-carbonylcarbonylamino), mono- or di-C _1-6 alkoxy-carbonylamino (eg tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino (eg pyridylamino), carbamoylamino ( mono - or di _{-C 1-6} alkyl - carbamoyl) amino group (e.g., methylcarbamoyl Carbamoylamino), (mono - or di _{-C 7-16} aralkyl - carbamoyl) amino group (e.g., benzylcarbamoyl _{amino), C 1-6} alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), _{C 6 -14} arylsulfonylamino group (eg, phenylsulfonylamino), (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino group (eg, N-acetyl-N-methylamino), (C _1-6 And alkyl) (C _6-14 aryl-carbonyl) amino groups (eg, N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substituted carbamoyl group” include, for example, “C _1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group A. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, _C1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di _{-C 1-6} alkyl - carbamoyl group and mono- - or di _{-C 7-16} aralkyl - 1 or 2 substituents selected from a carbamoyl group The have include a carbamoyl group which may.
Preferable examples of carbamoyl group which may be substituted include carbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _2-6 alkenyl-carbamoyl group (eg, diallyl carbamoyl group ), Mono- or di-C _3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl), mono- or Di-C _7-16 aralkyl-carbamoyl group, mono- or di-C _1-6 alkyl-carbonyl-carbamoyl group (eg, acetylcarbamoyl, propionylcarbamoyl), mono- or di-C _6-14 aryl-carbonyl-carbamoyl Group (eg benzoylcarbamoyl) And 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

In the present specification, examples of the “optionally substituted thiocarbamoyl group” include, for example, “C _1-6 alkyl which may have 1 to 3 substituents selected from Substituent Group A. Group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _7-16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C _1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di _{-C 1-6} alkyl - carbamoyl group and mono- - or di _{-C 7-16} aralkyl - one or two location selected from a carbamoyl group Have a group "include good thiocarbamoyl group.
Preferred examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C _1-6 alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio Carbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _2-6 alkenyl-thiocarbamoyl group (eg, diallyl thiocarbamoyl), mono- or di-C _3-10 cycloalkyl-thiocarbamoyl group ( Examples: cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14 aryl-thiocarbamoyl (eg phenylthiocarbamoyl), mono- or di-C _7-16 aralkyl-thiocarbamoyl (eg , Benzylthioca Bamoiru, phenethyl thio carbamoyl), mono - or di _{-C 1-6} alkyl - carbonyl - thiocarbamoyl group (e.g., acetyl thiocarbamoyl, propionylthio carbamoyl), mono - or di _{-C 6-14} aryl - carbonyl - thiocarbamoyl And groups such as benzoylthiocarbamoyl, 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups such as pyridylthiocarbamoyl.

In the present specification, as the "optionally substituted sulfamoyl group", for example, a "C _1-6 alkyl group which may have 1 to 3 substituents selected from Substituent group A" , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, _C1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di _{-C 1-6} alkyl - carbamoyl group and mono- - or di _{-C 7-16} aralkyl - 1 or 2 substituents selected from a carbamoyl group Have a "include sulfamoyl group.
Preferred examples of sulfamoyl group which may be substituted include sulfamoyl group and mono- or di-C _1-6 alkyl-sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethyl Sulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C _2-6 alkenyl-sulfamoyl group (eg, diallylsulfamoyl), mono- or di-C _3-10 cycloalkyl- Sulfamoyl group (eg, cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C _6-14 aryl-sulfamoyl group (eg, phenylsulfamoyl), mono- or di-C _7-16 aralkyl- Sulfamoyl group (eg benzylsulfamoyl, phenethylsulfamoy ), Mono - or di _{-C 1-6} alkyl - carbonyl - sulfamoyl group (e.g., acetyl sulfamoyl, propionitrile acylsulfamoyl), mono - or di _{-C 6-14} aryl - carbonyl - sulfamoyl group (e.g., benzoyl And sulfamoyl), 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridylsulfamoyl).

In the present specification, examples of the “optionally substituted hydroxy group” include, for example, “C _1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group A. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group, C _{7 -16} aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, _C1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl Group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _7-16 aralkyl-carbamoyl group, C _1-6 alkylsulfonyl group and C _The hydroxy group which may have "a substituent chosen from _6-14 arylsulfonyl groups" is mentioned.
Preferred examples of the hydroxy group which may be substituted include a hydroxy group, a C _1-6 alkoxy group, and a C _2-6 alkenyloxy group (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy) ), C _3-10 cycloalkyloxy group (eg, cyclohexyloxy), C _6-14 aryloxy group (eg, phenoxy, naphthyloxy), C _7-16 aralkyloxy group (eg, benzyloxy, phenethyloxy), C _1-6 alkyl-carbonyloxy group (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C _6-14 aryl-carbonyloxy group (eg, benzoyloxy), C _7-16 aralkyl- A carbonyloxy group (eg benzyl carbonyl oxide ), 5 to 14-membered aromatic heterocyclic carbonyloxy group (e.g., nicotinoyl oxy), 3 to 14-membered non-aromatic heterocyclic carbonyloxy group (e.g., piperidinylcarbonyl oxy), C _1-6 alkoxy - carbonyl Oxy group (eg, tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), carbamoyloxy group, C _1-6 alkyl-carbamoyloxy group (eg, methylcarbamoyloxy), C _7-16 aralkyl-carbamoyloxy group (eg, benzylcarbamoyloxy), C _1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy, ethylsulfonyloxy), C _6-14 arylsulfonyloxy group (eg, phenylsulfonyl) Oxy).

In the present specification, examples of the “optionally substituted sulfanyl group” include, for example, “C _1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group A. , C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl-carbonyl group, C _6-14 aryl-carbonyl group and 5 to Examples thereof include sulfanyl group which may have a substituent selected from 14-membered aromatic heterocyclic groups, and halogenated sulfanyl group.
Preferable examples of the optionally substituted sulfanyl group, sulfanyl (-SH) _{group, C 1-6} alkylthio _{group, C 2-6} alkenylthio group (e.g., allyl, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C _3-10 cycloalkylthio group (eg, cyclohexylthio), C _6-14 arylthio group (eg, phenylthio, naphthylthio), C _7-16 aralkylthio group (eg, benzylthio, phenethylthio), C _1-6 alkyl-carbonylthio group (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C _6-14 aryl-carbonylthio group (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio group (Eg, pyridylthio), halogenated thio (eg, pentafluorothio) E) can be mentioned.

In the present specification, examples of the “optionally substituted silyl group” include, for example, “C _1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group A. And silyl groups optionally having 1 to 3 substituents selected from C _2-6 alkenyl groups, C _3-10 cycloalkyl groups, C _6-14 aryl groups and C _7-16 aralkyl groups It can be mentioned.
Preferred examples of the silyl group which may be substituted include tri-C _1-6 alkylsilyl groups (eg, trimethylsilyl, tert-butyl (dimethyl) silyl).
In the present specification, as the "C _1-6 alkylene group", for example, -CH ₂ -,-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -,-(CH ₂ ) ₄ -,-(CH _{2) 5 -, - (CH} 2) 6 -, - CH (CH 3) -, - C (CH 3) 2 -, - CH (C 2 H 5) -, - CH (C 3 H 7) -, _{-CH (CH (CH 3) 2} ) -, - (CH (CH 3)) 2 -, - CH 2 -CH (CH 3) -, - CH (CH 3) -CH 2 -, - CH 2 -CH _{2 -C (CH 3) 2 -} , - C (CH 3) 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -C (CH 3) 2 -, - C (CH 3) 2 -CH ₂ -CH ₂ -CH ₂ - and the like.
In the present specification, the _{"C 2-6} alkenylene group", for _{example, -CH = CH -, - CH} 2 -CH = CH -, - CH = CH-CH 2 -, - C (CH 3) 2 - _{CH = CH -, - CH =} CH-C (CH 3) 2 -, - CH 2 -CH = CH-CH 2 -, - CH 2 -CH 2 -CH = CH -, - CH = CH-CH 2 - _{CH 2 -, - CH = CH} -CH = CH -, - CH = CH-CH 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -CH = CH- and the like.
In the present specification, examples of the "C _2-6 alkynylene group" include -C≡C-, -CH ₂ -C≡C-, -C≡C-CH _2- , and -C (CH ₃ ) _{2- C≡C -, - C≡C-C (} CH 3) 2 -, - CH 2 -C≡C-CH 2 -, - CH 2 -CH 2 -C≡C -, - C≡C-CH 2 - _{CH 2 -, - C≡C-C≡C} -, - C≡C-CH 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -C≡C- , and the like.

In the present specification, examples of the "hydrocarbon ring" include a C _6-14 aromatic hydrocarbon ring, a C _3-10 cycloalkane, and a C _3-10 cycloalkene.
In the present specification, examples of the "C _6-14 aromatic hydrocarbon ring" include benzene and naphthalene.
In the present specification, examples of “C _3-10 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.
In the present specification, examples of “C _3-10 cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
In the present specification, examples of the “heterocycle” include aromatic heterocycles containing, as ring-constituting atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms in addition to carbon atoms, and Non-aromatic heterocycles are mentioned.

In the present specification, the “aromatic heterocycle” is, for example, a 5- to 14-membered member containing 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms in addition to carbon atoms as ring-constituting atoms Preferably, a 5- to 10-membered aromatic heterocycle is mentioned. Preferred examples of the "aromatic heterocycle" include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadidi 5- to 6-membered monocyclic aromatic heterocycles such as azole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine and the like;
Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, Imidazo pyrimidine, thieno pyrimidine, furo pyrimidine, pyrrolo pyrimidine, pyrazolo pyrimidine, oxazolo pyrimidine, thiazolo pyrimidine, pyrazolo pyrimidine, pyrazolo triazine, naphtho [2,3-b] thiophene, phenoxathiin, indole, Isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, cal Tetrazole, beta-carboline, phenanthridine, acridine, phenazine, phenothiazine, 8 to 14 membered fused polycyclic, such as phenoxazine (preferably 2 or tricyclic) and aromatic heterocycle.

In the present specification, the "non-aromatic heterocycle" is, for example, a 3- to 14-membered member containing, as a ring-constituting atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atoms. Non-aromatic heterocyclic rings (preferably 4 to 10 members) can be mentioned. Preferable examples of the "non-aromatic heterocyclic ring" include aziridine, oxirane, thiiran, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline. , Thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepanine, 3 such as diazepam, azepine, azocan, diazocan and oxepane 8-membered monocyclic non-aromatic heterocyclic ring and;
Dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydronaphtho [2,3-b] thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno [2 , 3-c] pyridine, tetrahydrobenzoazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenothiazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline , Tetrahydroacridine, tetrahydrophenazine, tetrahydrothi Xanthene, 9 to 14 membered fused polycyclic, such as octahydro-isoquinoline (preferably 2 or tricyclic) non-aromatic heterocyclic ring.
In the present specification, as the "nitrogen-containing heterocycle", among the "heterocycles", those containing at least one or more nitrogen atoms as ring-constituting atoms can be mentioned.

  In the present specification, examples of the "nitrogen-containing aromatic heterocyclic group" further include N-oxide-pyridine.

Preferred examples of R ¹ , R ² , R ^3a , R ^3b , R ^4a , R ^4b , X and L in formula (I) are shown below.
R ¹ is preferably
(1) (i) hydroxy group,
(Ii) (a) hydroxy group,
(B) _C1-6 alkoxy group (especially methoxy),
(C) cyano group,
(D) optionally halogenated C _3-10 cycloalkyl
Group (especially cyclobutyl),
(E) 5- to 6-membered monocyclic aromatic heterocyclic group (especially pyridyl),
(F) 3- to 8-membered monocyclic non-aromatic heterocyclic group (especially morpholine
Nil),
and
(G) _{(A) C 1-6} alkyl group (particularly, methyl), and
_{(B) C 1-6} alkyl - carbonyl group (especially, acetyl
Le)
Even if it is mono- or di-substituted by a substituent selected from
Good amino group
And C _1-6 alkyl group optionally substituted by 1 to 3 substituents selected from (especially methyl, ethyl, propyl, tert-
Butyl, 2,2-dimethylpropyl, 3,3-dimethylbutyl),
(Iii) C _1-6 alkoxy group (especially methoxy),
(Iv) optionally halogenated C _3-10 cycloalkyl group (especially
, Cyclopropyl, cyclobutyl, cyclohexyl),
(V) C _6-14 aryl group (especially phenyl) which may have 1 to 7, preferably 1 to 5, and more preferably 1 to 3 halogen atoms (especially chlorine atoms)
(Vi) 1 to 3 (especially 1) C _1-6 alkyl groups (especially methyl)
A 5- to 6-membered monocyclic aromatic heterocyclic group which may be substituted
(Especially pyrrolyl, pyrazolyl, isothiazolyl, oxazolyl
, Isoxazolyl, pyridyl, thiadiazolyl),
(Vii) 3- to 8-membered monocyclic non-aromatic heterocyclic group (especially oxetanyl),
(Viii) C _7-16 aralkyl group (especially benzyl, phenethyl),
And (ix) C _7-16 aralkyloxy group (especially benzyloxy)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from
_{(2) C 1-6} alkyl - carbonyl group (especially acetyl),
(3) carboxy group,
_{(4) C 1-6} alkoxy - carbonyl group (especially, ethoxycarbonyl) is, or (5) a cyano group.
R ¹ is more preferably a carbamoyl group.

R ² is preferably
(I) (1) halogen atom (in particular, chlorine atom, bromine atom),
(2) cyano group,
_{(3) C 1-6} alkyl group (particularly, methyl),
(4) (a) hydroxy group, and
(B) _C1-6 alkoxy group (especially methoxy, ethoxy)
May be substituted by 1 to 3 substituents selected from
C _1-6 alkyl group (especially methyl, ethyl, 2-methylpropyl)
And carbamoyl which may be mono- or di-substituted with
(5) C _3-10 cycloalkyl-carbamoyl group (especially cyclopropyl)
Ropircarbamoyl),
(6) carboxy group,
(7) _C1-6 alkoxy-carbonyl group (especially ethoxycarbonyl)
Le),
(8) (a) hydroxy group, and
(B) _C1-6 alkoxy group (especially methoxy)
1 to 5, preferably 1 to 3 selected from
Preferably 3 to 14 optionally substituted by 1 substituent
-Membered non-aromatic heterocyclic carbonyl group (especially, 3- to 8-membered monocyclic ring-containing group)
Nitrogen non-aromatic heterocyclic carbonyl group (preferably azetidinyl)
Carbonyl, pyrrolidinyl carbonyl, piperidinyl carboni
Le, morpholinylcarbonyl)),
(9) carbamimidoyl group (amidino group), and (10) _{(i) C 1-6} alkyl group (particularly, methyl),
(Ii) (a) hydroxy group, and
(B) _C1-6 alkoxy group (especially methoxy)
Substituted with 1 to 3 substituents selected from
_Optionally substituted C _1-6 alkyl-carbonyl group (especially
Acetyl, propanoyl, 2-methylpropanoyl),
(Iii) may be substituted by 1 to 3 hydroxy groups
C _3-10 cycloalkyl-carbonyl group (especially cyclo
Propylcarbonyl),
(Iv) C _1-6 alkoxy-carbonyl group (especially ethoxy
Carbonyl), and
(V) 1 to 3 C _1-6 alkyl groups (especially methyl)
Optionally substituted oxetanyl-carbonyl group
May be mono- or di-substituted with a substituent selected from
Amino group
5 optionally substituted by 1 to 3 substituents selected from
To 6-membered nitrogen-containing aromatic heterocyclic groups (preferably, 5- to 6-membered single-membered
Cyclic nitrogen-containing aromatic heterocycle (especially pyrazolyl, pyridyl, N-o
Oxido-pyridyl, thiazolyl)),
(II) (1) halogen atom (especially bromine atom),
(2) cyano group,
(3) substituted with 1 to 3 halogen atoms (especially fluorine atoms)
_Optionally substituted C _1-6 alkyl group (especially methyl),
(4) 3- to 14-membered non-aromatic heterocycle-carbonyl group (especially, molar
Holinyl carbonyl),
(5) 1 to 3 C _1-6 alkoxy groups (especially methoxy,
C _1-6 alkyl group optionally substituted by
, Methyl, ethyl) may be mono- or di-substituted
Carbamoyl group,
(6) C _1-6 alkyl-sulfonyl group (especially methylsulfonyl)
, Propylsulfonyl, isopropylsulfonyl), and (7) substituted with 1 to 5 halogen atoms (particularly, fluorine atoms)
Optionally substituted sulfanyl group (especially pentafluorothio)
Or C _6-14 aryl group (in particular, phenyl) optionally substituted by 1 to 3 substituents selected from: (III) 1 to 3 C _1-6 alkoxy groups (in particular, ethoxy) Replace by
_Optionally substituted C _1-6 alkyl group (especially methyl, ethyl,
Propyl)
It is.
More preferably, R ² is
(I) _{(1) C 1-6} alkyl group (particularly, methyl),
(2) (i) hydroxy group, and
(Ii) C _1-6 alkoxy group (especially methoxy)
Substituted with 1 to 3 (particularly, 1) substituents selected from
_Optionally substituted C _1-6 alkyl group (especially methyl, ethyl,
May be mono- or di-substituted with 2-methylpropyl)
Carbamoyl group, and (3) (i) C _1-6 alkyl group (especially methyl),
(Ii) substituted with 1 to 3 (especially 1) hydroxy group
_Optionally substituted C _1-6 alkyl-carbonyl group (especially
Acetyl, 2-methylpropanoyl),
(Iii) substituted with 1 to 3 (especially 1) hydroxy group
_{Optionally substituted} C _3-10 cycloalkyl-carbonyl group
(Especially cyclopropylcarbonyl), and
(Iv) 1 to 3 C _1-6 alkyl groups (especially methyl)
Optionally substituted oxetanyl-carbonyl group
Are optionally substituted mono- or di-substituted with a substituent selected from
Group,
Or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents (in particular, pyrazolyl, pyridyl, N-oxido-pyridyl), or (II) 3 to 14 _6-14 aryl group (especially phenyl) which may be substituted with a membered non-aromatic heterocycle-carbonyl group (especially morpholinyl carbonyl)
It is.
More preferably, R ² is
_{(1) C 1-6} alkyl group (particularly, methyl),
(2) (i) hydroxy group, and (ii) _C1-6 alkoxy group (especially methoxy)
And C 1 _-6 alkyl group (in particular, 2-methylpropyl, ethyl) optionally substituted by 1 to 3 substituents selected from
Or a carbamoyl group which may be di-substituted, and (3) a C _3-10 cycloalkyl-carbonylamino group (in particular, cyclo
Propylcarbonylamino)
A 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from (in particular, pyrazolyl, pyridyl, N-oxide-pyridyl)
It is.

R ^3a is preferably a hydrogen atom or a C _1-6 alkyl group (especially methyl).
R ^3a is more preferably a hydrogen atom.

R ^4a is preferably a hydrogen atom.

R ^3b is preferably a hydrogen atom or a C _1-6 alkyl group (especially methyl).
R ^3b is more preferably a hydrogen atom.

R ^4b is preferably a hydrogen atom.

Also, R ^3b and R ^4b preferably together form a double bond.

It is particularly preferable that all of R ^3a , R ^4a , R ^3b and R ^4b are a hydrogen atom.

  X is preferably N or CH, more preferably CH.

As the “spacer” for L, a chain atom group having a main chain formed of 1 to 3 atoms selected from the group consisting of carbon, oxygen, nitrogen and sulfur is preferable, and —O—, — S-, -SO- or -SO ₂ -is more preferable, and -O-, -S- or -SO ₂ -is more preferable.
L is preferably -O-, -S-, -SO-, -SO ₂ -or a bond, more preferably -O-, -S- or -SO _2- , and still more preferably -O- -.

Preferred specific examples of compound (I) include the following:
Compound (A-p):
R ¹ is
(1) (i) hydroxy group,
(Ii) (a) hydroxy group,
(B) _C1-6 alkoxy group (especially methoxy),
(C) cyano group,
(D) _C3-10 cycloalkyl group which may be halogenated
(Especially difluorocyclobutyl),
(E) 5- to 6-membered monocyclic aromatic heterocyclic group (especially pyridyl),
(F) 3- to 8-membered monocyclic non-aromatic heterocyclic group (especially morpholini
Le), and
(G) _{(A) C 1-6} alkyl group (particularly, methyl), and
_{(B) C 1-6} alkyl - carbonyl group (especially acetyl)
Even if it is mono- or di-substituted by a substituent selected from
Substituted with 1 to 3 substituents selected from good amino groups
Optionally C _1-6 alkyl group (especially methyl, ethyl, prop
, Tert-butyl, 2,2-dimethylpropyl, 3,3-di
Methyl butyl),
(Iii) C _1-6 alkoxy group (especially methoxy),
(Iv) optionally halogenated C _3-10 cycloalkyl group (especially, cyclopropyl, difluorocyclobutyl, cyclohexyl),
(V) C _6-14 aryl group (especially phenyl) which may have 1 to 7, preferably 1 to 5, and more preferably 1 to 3 halogen atoms (especially chlorine atoms)
(Vi) a 5- to 6-membered monocyclic aromatic heterocyclic group which may be substituted by 1 to 3 (particularly, 1) C _1-6 alkyl group (particularly, methyl)
In particular pyrrolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, thiadiazolyl),
(Vii) 3- to 8-membered monocyclic non-aromatic heterocyclic group (especially oxetanyl),
(Viii) C _7-16 aralkyl group (especially benzyl, phenethyl), and (ix) C _7-16 aralkyloxy group (especially benzyloxy)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from
_{(2) C 1-6} alkyl - carbonyl group (especially acetyl),
(3) carboxy group,
(4) a C _1-6 alkoxy-carbonyl group (particularly ethoxycarbonyl) or (5) a cyano group;
R ² is
(I) (1) halogen atom (in particular, chlorine atom, bromine atom),
(2) cyano group,
_{(3) C 1-6} alkyl group (particularly, methyl),
(4) (a) hydroxy group, and
(B) _C1-6 alkoxy group (especially methoxy, ethoxy)
May be substituted by 1 to 3 substituents selected from
C _1-6 alkyl group (especially methyl, ethyl, 2-methylpropyl)
And carbamoyl which may be mono- or di-substituted with
(5) C _3-10 cycloalkyl-carbamoyl group (especially cyclopropyl)
Ropircarbamoyl),
(6) carboxy group,
(7) _C1-6 alkoxy-carbonyl group (especially ethoxycarbonyl)
Le),
(8) (a) hydroxy group, and
(B) _C1-6 alkoxy group (especially methoxy)
1 to 5, preferably 1 to 3 selected from
Preferably 3 to 14 optionally substituted by 1 substituent
-Membered non-aromatic heterocyclic carbonyl group (especially, 3- to 8-membered monocyclic ring-containing group)
Nitrogen non-aromatic heterocyclic carbonyl group (preferably azetidinyl)
Carbonyl, pyrrolidinyl carbonyl, piperidinyl carboni
Le, morpholinylcarbonyl)),
(9) carbamimidoyl group (amidino group), and (10) _{(i) C 1-6} alkyl group (particularly, methyl),
(Ii) (a) hydroxy group, and
(B) _C1-6 alkoxy group (especially methoxy)
Substituted with 1 to 3 substituents selected from
_Optionally substituted C _1-6 alkyl-carbonyl group (especially
Acetyl, propanoyl, 2-methylpropano
),
(Iii) may be substituted by 1 to 3 hydroxy groups
C _3-10 cycloalkyl-carbonyl group (especially
Propyl carbonyl),
_{(Iv) C 1-6} alkoxy - carbonyl group (especially, Etokishika
Rubonyl), and
(V) 1 to 3 C _1-6 alkyl groups (especially methyl)
Optionally substituted oxetanyl-carbonyl group
May be mono- or di-substituted with a substituent selected from
Amino group
5 optionally substituted by 1 to 3 substituents selected from
To 6-membered nitrogen-containing aromatic heterocyclic group (preferably, 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic ring (especially pyrazolyl, pyridyl, N-oxy-pyridyl, thiazolyl)),
(II) (1) halogen atom (especially bromine atom),
(2) cyano group,
(3) substituted with 1 to 3 halogen atoms (especially fluorine atoms)
_Optionally substituted C _1-6 alkyl group (especially methyl),
(4) 3- to 14-membered non-aromatic heterocycle-carbonyl group (especially, molar
Holinyl carbonyl),
(5) 1 to 3 C _1-6 alkoxy groups (especially methoxy,
C _1-6 alkyl group optionally substituted by
Methyl, ethyl) which may be mono- or di-substituted
Lvamoyl group,
(6) C _1-6 alkyl-sulfonyl group (especially methylsulfonyl)
, Propylsulfonyl, isopropylsulfonyl), and (7) substituted with 1 to 5 halogen atoms (particularly, fluorine atoms)
Optionally substituted sulfanyl group (especially pentafluorothio)
May be substituted by 1 to 3 substituents selected from
A C _6-14 aryl group (especially phenyl); or (III) a C _1-6 alkyl group (especially methyl) which may be substituted with 1 to 3 C _1-6 alkoxy groups (especially ethoxy) Ethyl, pill)
And
R ^3a is a hydrogen atom or a C _1-6 alkyl group (especially methyl);
R ^4a is a hydrogen atom;
R ^3b is a hydrogen atom or a C _1-6 alkyl group (especially methyl), and R ^4b is a hydrogen atom, or R ^3b and R ^4b together form a double bond And
X is N or CH;
L is -O-, -S-, -SO-, -SO ₂ -or a bond,
Compound (I).

Compound (A):
R ¹ is
(1) (i) hydroxy group,
(Ii) (a) hydroxy group,
(B) _C1-6 alkoxy group (especially methoxy),
(C) cyano group,
(D) _C3-10 cycloalkyl group which may be halogenated
(Especially difluorocyclobutyl),
(E) 5- to 6-membered monocyclic aromatic heterocyclic group (especially pyridyl),
(F) 3- to 8-membered monocyclic non-aromatic heterocyclic group (especially morpholini
Le), and
(G) _{(A) C 1-6} alkyl group (particularly, methyl), and
_{(B) C 1-6} alkyl - carbonyl group (especially acetyl)
Even if it is mono- or di-substituted by a substituent selected from
Good amino group
And C _1-6 alkyl group optionally substituted by 1 to 3 substituents selected from (especially methyl, ethyl, propyl, tert-
Butyl, 2,2-dimethylpropyl, 3,3-dimethylbutyl),
(Iii) C _1-6 alkoxy group (especially methoxy),
(Iv) optionally halogenated C _3-10 cycloalkyl group (especially, cyclopropyl, difluorocyclobutyl, cyclohexyl),
(V) C _6-14 aryl group (especially phenyl) which may have 1 to 7, preferably 1 to 5, and more preferably 1 to 3 halogen atoms (especially chlorine atoms)
(Vi) a 5- to 6-membered monocyclic aromatic heterocyclic group which may be substituted by 1 to 3 (particularly, 1) C _1-6 alkyl group (particularly, methyl)
In particular pyrrolyl, pyrazolyl, oxazolyl, pyridyl, thiadiazolyl),
(Vii) 3- to 8-membered monocyclic non-aromatic heterocyclic group (especially oxetanyl),
(Viii) C _7-16 aralkyl group (especially benzyl, phenethyl),
And (ix) C _7-16 aralkyloxy group (especially benzyloxy)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from
_{(2) C 1-6} alkyl - carbonyl group (especially acetyl),
(3) carboxy group,
(4) a C _1-6 alkoxy-carbonyl group (particularly ethoxycarbonyl) or (5) a cyano group;
R ² is
(I) (1) halogen atom (in particular, chlorine atom, bromine atom),
(2) cyano group,
_{(3) C 1-6} alkyl group (particularly, methyl),
(4) (a) hydroxy group, and
(B) _C1-6 alkoxy group (especially methoxy, ethoxy)
May be substituted by 1 to 3 substituents selected from
C _1-6 alkyl group (especially methyl, ethyl, 2-methyl propiyl
Carbamoyl group which may be mono- or di-substituted with
(5) C _3-10 cycloalkyl-carbamoyl group (especially cyclopropyl)
Ropircarbamoyl),
(6) carboxy group,
(7) _C1-6 alkoxy-carbonyl group (especially ethoxycarbonyl)
Le),
(8) (a) hydroxy group, and
(B) _C1-6 alkoxy group (especially methoxy)
1 to 5, preferably 1 to 3 selected from
Preferably 3 to 14 optionally substituted by 1 substituent
-Membered non-aromatic heterocyclic carbonyl group (especially, 3- to 8-membered monocyclic ring-containing group)
Nitrogen non-aromatic heterocyclic carbonyl group (preferably azetidinyl)
Carbonyl, pyrrolidinyl carbonyl, piperidinyl carboni
Le, morpholinylcarbonyl)),
(9) carbamimidoyl group (amidino group), and (10) _{(i) C 1-6} alkyl group (particularly, methyl),
(Ii) (a) hydroxy group, and
(B) _C1-6 alkoxy group (especially methoxy)
Substituted with 1 to 3 substituents selected from
_Optionally substituted C _1-6 alkyl-carbonyl group (especially
Acetyl, propanoyl, 2-methylpropano
),
(Iii) may be substituted by 1 to 3 hydroxy groups
C _3-10 cycloalkyl-carbonyl group (especially
Propyl carbonyl),
_{(Iv) C 1-6} alkoxy - carbonyl group (especially, Etokishika
Rubonyl), and
(V) 1 to 3 C _1-6 alkyl groups (especially methyl)
Optionally substituted oxetanyl-carbonyl group
May be mono- or di-substituted with a substituent selected from
Amino group
5 optionally substituted by 1 to 3 substituents selected from
To 6-membered nitrogen-containing aromatic heterocyclic group (preferably, 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic ring (especially pyrazolyl, pyridyl, N-oxy-pyridyl, thiazolyl)),
(II) (1) halogen atom (especially bromine atom),
(2) cyano group,
(3) substituted with 1 to 3 halogen atoms (especially fluorine atoms)
_Optionally substituted C _1-6 alkyl group (especially methyl),
(4) 3- to 14-membered non-aromatic heterocycle-carbonyl group (especially, molar
Holinyl carbonyl),
(5) 1 to 3 C _1-6 alkoxy groups (especially methoxy,
C _1-6 alkyl group optionally substituted by
Methyl, ethyl) which may be mono- or di-substituted
Lvamoyl group,
(6) C _1-6 alkyl-sulfonyl group (especially methylsulfonyl)
, Propylsulfonyl, isopropylsulfonyl), and (7) substituted with 1 to 5 halogen atoms (particularly, fluorine atoms)
Optionally substituted sulfanyl group (especially pentafluorothio)
May be substituted by 1 to 3 substituents selected from
A C _6-14 aryl group (especially phenyl); or (III) a C _1-6 alkyl group (especially methyl) which may be substituted with 1 to 3 C _1-6 alkoxy groups (especially ethoxy) Ethyl, pill)
And
R ^3a , R ^3b , R ^4a and R ^4b are a hydrogen atom;
X is N or CH;
L is -O-, -S- or -SO _2- ,
Compound (I).

Compound (B):
R ¹ is a carbamoyl group;
R ² is
(I) _{(1) C 1-6} alkyl group (particularly, methyl),
(2) (i) hydroxy group, and
(Ii) C _1-6 alkoxy group (especially methoxy)
Substituted with 1 to 3 (particularly, 1) substituents selected from
_Optionally substituted C _1-6 alkyl group (especially methyl, ethyl,
May be mono- or di-substituted with 2-methylpropyl)
Carbamoyl group, and (3) (i) C _1-6 alkyl group (especially methyl),
(Ii) substituted with 1 to 3 (especially 1) hydroxy group
_Optionally substituted C _1-6 alkyl-carbonyl group (especially
Cetyl, 2-methylpropanoyl),
(Iii) substituted with 1 to 3 (especially 1) hydroxy group
_{Optionally substituted} C _3-10 cycloalkyl-carbonyl group (
In particular cyclopropylcarbonyl), and
(Iv) 1 to 3 C _1-6 alkyl groups (especially methyl)
Optionally substituted oxetanyl-carbonyl group
Are optionally substituted mono- or di-substituted with a substituent selected from
Group,
Or a 5- to 6-membered nitrogen-containing aromatic heterocyclic group optionally substituted by 1 to 3 substituents (in particular, pyrazolyl, pyridyl, N-oxido-pyridyl), or (II) 3 to 14 _6-14 aryl group (especially phenyl) which may be substituted with a membered non-aromatic heterocycle-carbonyl group (especially morpholinyl carbonyl)
And
X is CH;
Compound (A) wherein L is -O-.

Compound (C):
R ² is
_{(1) C 1-6} alkyl group (particularly, methyl),
(2) (i) hydroxy group, and (ii) _C1-6 alkoxy group (especially methoxy)
And C _1-6 optionally substituted with 1 to 3 substituents selected from
A carbamoyl group which may be mono- or di-substituted with an alkyl group (in particular, 2-methylpropyl, ethyl), and (3) a C _3-10 cycloalkyl-carbonylamino group (in particular, cyclopropylcarbonylamino)
A 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group (in particular, pyrazolyl, pyridyl, N-oxide-pyridyl) which may be substituted by 1 to 3 substituents selected from B).

The salt in compound (I) is preferably a pharmacologically acceptable salt, such as a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basic or acidic Salts with amino acids may be mentioned.
Preferable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts and ammonium salts.
Preferred examples of salts with organic bases are trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, Dicyclohexylamine and salts with N, N-dibenzylethylenediamine can be mentioned.
Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
Preferred examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid And salts with p-toluenesulfonic acid.
Preferred examples of salts with basic amino acids include salts with arginine, lysine and ornithine.
Preferred examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid.

  The process for producing the compound of the present invention is described below.

  The raw materials and reagents used in each step of the following production method, and the obtained compound may each form a salt. As such a salt, for example, the same salts as those of the aforementioned compound of the present invention can be mentioned.

  When the compound obtained in each step is a free compound, it can be converted to a target salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted to a free form or another type of desired salt by a method known per se.

  The compound obtained in each step may be used as the reaction solution or as a crude product and then used in the next reaction, or the compound obtained in each step may be concentrated from the reaction mixture according to a conventional method It can be isolated and / or purified by separation means such as crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography and the like.

  When the raw material of each process and the compound of a reagent are marketed, a commercial item can be used as it is.

  In the reaction of each step, the reaction time may vary depending on the reagent and solvent to be used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

  In the reaction of each step, the reaction temperature may vary depending on the reagent and solvent to be used, but unless otherwise specified, it is usually -78 ° C to 300 ° C, preferably -78 ° C to 150 ° C.

  In the reaction of each step, the pressure may differ depending on the reagent and solvent used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

  In the reaction of each step, for example, a microwave synthesizer such as Biotage's Initiator may be used. The reaction temperature may vary depending on the reagent and solvent to be used, but unless otherwise specified, it is usually room temperature to 300 ° C., preferably 50 ° C. to 250 ° C. The reaction time may vary depending on the reagent and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

  In the reaction of each step, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. When the reagent also serves as the reaction solvent, the amount of the solvent is used.

In the reaction of each step, unless otherwise specified, these reactions are carried out without solvent, or dissolved or suspended in a suitable solvent. Specific examples of the solvent include the solvents described in the examples, or the following.
Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol etc .;
Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc .;
Aromatic hydrocarbons: chlorobenzene, toluene, xylene etc .;
Saturated hydrocarbons: cyclohexane, hexane etc .;
Amides: N, N-dimethylformamide, N-methylpyrrolidone and the like;
Halogenated hydrocarbons: dichloromethane, carbon tetrachloride etc .;
Nitriles: acetonitrile, etc .;
Sulfoxides: dimethyl sulfoxide and the like;
Aromatic organic bases: pyridine and the like;
Acid anhydrides: acetic anhydride etc .;
Organic acids: Formic acid, acetic acid, trifluoroacetic acid etc .;
Inorganic acids: hydrochloric acid, sulfuric acid etc .;
Esters: Ethyl acetate etc .;
Ketones: acetone, methyl ethyl ketone etc .;
water.
The above solvents may be used as a mixture of two or more at an appropriate ratio.

When a base is used in the reaction of each step, for example, the bases shown below or the bases described in the examples are used.
Inorganic bases: sodium hydroxide, magnesium hydroxide etc .;
Basic salts: sodium carbonate, calcium carbonate, sodium hydrogen carbonate etc .;
Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]- 7-Undecene, imidazole, piperidine etc .;
Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc .;
Alkali metal hydrides: sodium hydride etc .;
Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide etc .;
Organic lithiums: n-butyllithium and the like.

When an acid or acidic catalyst is used in the reaction of each step, for example, the acid or acidic catalyst shown below, or the acid or acidic catalyst described in the examples is used.
Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid etc .;
Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .;
Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.

  Unless otherwise specified, the reaction of each step is a method known per se, for example, 5th Edition Experimental Chemistry Lecture, Volume 13 to Volume 19 (edited by The Chemical Society of Japan); New Experimental Chemistry Lecture, Volume 14 to 15 (Japan) Chemical Chemistry ed .; Precision Organic Chemistry Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankyodo); Revised Organic Personal Name Reaction Mechanism and Points (Hideo Togo, Kodansha); Organic Syntheses Collective Volume I ~ VII ( John Wiley & Sons, Inc .; Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental Procedures by Jie Jack Li, Oxford Universit Publishing); Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14 (Elsevier Japan Co., Ltd.); Organic synthesis strategies learned from personal name reaction (translated by Tomioka Kiyomi, published by Chemical Doujinshi); Methods described in Comprehensive Organic Transformations (VCH Publishers, Inc.) 1989, etc. Or, it is carried out according to the method described in the examples.

In each step, protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, Wiley-Interscience 2007, "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter G. M. Wuts Tyeme, Inc. 2004, “Protecting Groups, 3rd Ed.” (P. J. Kocienski), etc., or the method described in the examples.
Examples of protecting groups for hydroxyl group and phenolic hydroxyl group such as alcohol include, for example, ether type protecting groups such as methoxy methyl ether, benzyl ether, t-butyldimethylsilyl ether, tetrahydropyranyl ether and the like; carboxylic acid ester type protecting groups such as acetic acid ester Sulfonic acid ester type protective groups such as methanesulfonic acid ester; carbonate type protective groups such as t-butyl carbonate and the like.
Examples of the protecting group of the carbonyl group of aldehyde include an acetal type protecting group such as dimethyl acetal; and a cyclic acetal type protecting group such as cyclic 1,3-dioxane.
Examples of the protecting group of carbonyl group of ketone include ketal type protecting group such as dimethyl ketal; cyclic ketal type protecting group such as cyclic 1,3-dioxane; oxime type protecting group such as O-methyloxime; And hydrazone type protective groups such as dimethyl hydrazone.
Examples of protecting groups for carboxyl groups include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N, N-dimethylamide.
Examples of the thiol protecting group include ether-type protecting groups such as benzyl thioether; and ester-type protecting groups such as thioacetic acid ester, thiocarbonate and thiocarbamate.
Examples of protecting groups for amino heterocycles and aromatic heterocycles such as imidazole, pyrrole and indole include carbamate protecting groups such as benzyl carbamate; amide protecting groups such as acetamide; alkylamines such as N-triphenylmethylamine Type protecting groups, sulfonamide type protecting groups such as methane sulfonamide, and the like.
Removal of the protecting group is carried out by a method known per se, such as acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide) (Trimethylsilyl bromide), a reduction method, or the like.

  When performing a reduction reaction in each step, the reducing agent used is lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride Metal hydrides such as triacetoxyborohydride and tetramethylammonium hydride; boranes such as borane-tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid and the like. In the case of reducing a carbon-carbon double bond or triple bond, there is a method using a catalyst such as palladium-carbon or Lindlar catalyst.

  When an oxidation reaction is carried out in each step, examples of the oxidizing agent used include m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, peracids such as t-butyl hydroperoxide, etc .; tetrabutyl ammonium perchlorate, etc. Perchlorates; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodic acids such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese dioxide Reagents having manganese such as potassium manganate; Leads such as lead tetraacetate; pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), reagents having chromium such as Jones reagent; N-bromosuccinimide (NBS) Halogen compounds such as: oxygen; ozone; sulfur trioxide / pyridine complex; Beam; dioxide Zeren; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

  When performing radical cyclization reaction in each process, as a radical initiator used, azo compounds such as azobisisobutyronitrile (AIBN); 4-4'-azobis-4-cyanopentanoic acid (ACPA) Water soluble radical initiators; triethyl boron in the presence of air or oxygen; benzoyl peroxide and the like. Further, as a radical reaction agent to be used, tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and the like can be mentioned.

  When carrying out a Wittig reaction in each step, examples of the Wittig reagent used include alkylidene phosphoranes and the like. The alkylidene phosphoranes can be prepared by methods known per se, for example, by reacting a phosphonium salt with a strong base.

  When performing the Horner-Emmons reaction in each step, as reagents used, phosphonoacetic acid esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; bases such as alkali metal hydrides and organic lithiums It can be mentioned.

  When carrying out the Friedel-Crafts reaction in each step, examples of reagents used include Lewis acids and acid chlorides or alkylating agents (eg, halogenated alkyls, alcohols, olefins, etc.). Alternatively, instead of the Lewis acid, an organic acid or inorganic acid can be used, and instead of the acid chloride, an acid anhydride such as acetic anhydride can be used.

  When performing an aromatic nucleophilic substitution reaction in each step, a nucleophile (eg, amines, imidazole etc.) and a base (eg, basic salts, organic bases etc.) are used as reagents.

  When performing nucleophilic addition reaction with carbanion, nucleophilic 1,4-addition reaction with carbanion (Michael addition reaction), or nucleophilic substitution reaction with carbanion in each step, a base used to generate carbanion And organic lithiums, metal alkoxides, inorganic bases, organic bases and the like.

  When performing Grignard reaction in each process, Grignard reagents include aryl magnesium halides such as phenyl magnesium bromide; and alkyl magnesium halides such as methyl magnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with magnesium metal with ether or tetrahydrofuran as a solvent.

  When performing Knoevenagel condensation reaction in each step, as reagents, active methylene compounds (eg, malonic acid, diethyl malonate, malononitrile etc.) and bases (eg, organic bases, etc.) sandwiched between two electron withdrawing groups Metal alkoxides, inorganic bases) are used.

  When Vilsmeier-Haack reaction is performed in each step, phosphoryl chloride and an amide derivative (eg, N, N-dimethylformamide etc.) are used as reagents.

  When carrying out the azidation reaction of alcohols, alkyl halides and sulfonic acid esters in each step, examples of the azidation agent to be used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide and the like. For example, in the case of azide alcohol, there are a method using diphenylphosphoryl azide and 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU), a method using trimethylsilyl azide and a Lewis acid, and the like.

  When the reductive amination reaction is carried out in each step, the reducing agent used includes sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde as well as aldehydes such as acetaldehyde and ketones such as cyclohexanone. When the substrate is a carbonyl compound, the amines to be used include ammonia, primary amines such as methylamine; secondary amines such as dimethylamine, and the like.

  When the Mitsunobu reaction is performed in each step, azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

  When performing esterification reaction, amidation reaction, or urea conversion reaction in each step, as reagents used, acyl chloride such as acid chloride and acid bromide; acid anhydride, active ester, sulfuric acid ester And activated carboxylic acids. Carbodiimide-based condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD) as an activating agent for carboxylic acid; 4- (4,6-dimethoxy-1,3,5-) Triazine-based condensing agents such as triazin-2-yl) -4-methylmorpholinium chloride-n-hydrate (DMT-MM); Carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenyl Phosphorus azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukayama reagent); thionyl chloride; haloformic acid such as ethyl chloroformate Lower alkyl; O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-te Tramethyluronium hexafluorophosphate (HATU); sulfuric acid; or a combination thereof. When a carbodiimide type condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like may be further added to the reaction.

  When a coupling reaction is carried out in each step, the metal catalyst used is palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethyl) Phosphine compounds such as phosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1'-bis (diphenyl phosphino) ferrocene palladium (II) chloride, palladium (II) acetate etc; Nickel compounds such as phenyl phosphine) nickel (0); rhodium compounds such as tris (triphenyl phosphine) rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper (I) iodide; platinum compounds etc. Be Furthermore, a base may be added to the reaction, and such bases include inorganic bases, basic salts and the like.

  When thiocarbonylation is carried out in each step, typically, diphosphorus pentasulfide is used as a thiocarbonylating agent, but in addition to diphosphorus pentasulfide, 2,4-bis (4-methoxyphenyl) A reagent having a 1,3,2,4-dithiadiphosphetan-2,4-disulfide structure such as 1,3,2,4-dithiadiphosphetan-2,4-disulfide (Lawesson's reagent) You may use.

  When performing Wohl-Ziegler reaction in each process, as a halogenating agent to be used, N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride and the like Can be mentioned. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile or the like to the reaction.

  When performing a halogenation reaction of a hydroxy group in each step, as a halogenating agent to be used, an acid halide of a hydrohalic acid and an inorganic acid, specifically, in chlorination, hydrochloric acid, thionyl chloride, oxy For bromination, such as phosphorus chloride, 48% hydrobromic acid and the like can be mentioned. Alternatively, a method of obtaining a halogenated alkyl from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used. Alternatively, a method may be used in which a halogenated alkyl is synthesized through a two-step reaction in which an alcohol is converted to a sulfonic acid ester and then reacted with lithium bromide, lithium chloride or sodium iodide.

  When the Arbuzov reaction is performed in each step, examples of the reagent to be used include alkyl halides such as ethyl bromoacetate; and phosphites such as triethyl phosphite and tri (isopropyl) phosphite.

  When a sulfone esterification reaction is performed in each step, examples of the sulfonating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic acid anhydride, p-toluenesulfonic acid anhydride and the like.

  When performing a hydrolysis reaction in each step, an acid or a base is used as a reagent. Moreover, when performing the acid hydrolysis reaction of t-butyl ester, formic acid, triethylsilane, etc. may be added in order to trap by-product t-butyl cation reductively.

  When dehydration reaction is carried out in each step, examples of the dehydrating agent used include sulfuric acid, diphosphorus pentaoxide, phosphorus oxychloride, N, N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

The leaving group to be used in each step is, for example, a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C _1-6 alkoxy group (eg, methoxy etc.), C _6-14 aryl Oxy group (eg, phenoxy etc.), optionally substituted acyl-oxy group (eg, acetyloxy, benzoyloxy etc.), optionally substituted C _1-6 alkoxysulfonyloxy group (eg, methoxysulfonyloxy Etc.), C _1-6 alkylsulfonyl-oxy group which may be halogenated (eg, methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy (triflate), etc.), even if substituted good C _6-14 arylsulfonyl - group [e.g., C _1-6 alkyl group (e.g., methyl, ethyl, propyl , Isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl, etc.), C _1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, pentyloxy, And C _6-14 arylsulfonyloxy group which may have 1 to 3 substituents selected from hexoxy groups, etc., and a nitro group, and the like, and specific examples thereof include benzenesulfonyloxy, m and the like. -Nitrobenzenesulfonyloxy, p-toluenesulfonyloxy, naphthylsulfonyloxy etc.] and the like.

Below, the manufacturing method of compound (I) is demonstrated.
Each symbol in the following reaction formulas is as defined above unless otherwise indicated. The starting compounds can be readily obtained commercially from commercially available products if the specific process is not described, or can be produced by a method known per se or a method analogous thereto.
[Manufacturing method 1]
Among the compounds (I), compounds (Ia) in which X is CR ⁵ and R ^3b and R ^4b are independently a hydrogen atom or a substituent are the following production methods or compounds from compound (II), or It can manufacture by the method according to this.

In the formula, Y ¹ and Y ² represent the aforementioned leaving group.
In the formula, M ¹ represents a hydrogen atom or an alkali metal atom (eg, lithium atom, sodium atom, potassium atom, rubidium atom, cesium atom, francium atom).
In the formula, Y ³ represents a hydrogen atom, or an optionally substituted C _1-6 alkyl group (eg, benzyl group, tert-butyl group, etc.).
In the formulae, R ^{3b ′} and R ^{4b ′} independently represent a hydrogen atom or a substituent.
Other symbols are as defined above.

Compound (II) can be commercially available, or can be produced by a method known per se [for example, a method described in patent document (WO 2001/074823) or the like] or a method analogous thereto.
Compound (IVa), compound (IVb), or a mixture thereof can be produced by the carbonylation reaction of compound (II) with compound (III). The carbonylation reaction can also be carried out in the presence of an acid or a base.
Compound (V) can be produced by the reaction of converting compound (IVa), compound (IVb), or a mixture thereof to a leaving group. The conversion reaction to a leaving group is a method known per se, for example, Wiley-Interscience 2007, "Protective Groups in Organic Synthesis, 4 ^th Ed." (Theodora W. Greene, Peter GM Wuts); Thieme 2004 It performed in accordance with "Protecting Groups, 3 ^rd Ed." (PJ Kocienski Author) methods are described, for example, or the method described in example. The reaction for converting into a halogen atom as a leaving group can also be carried out by the above-mentioned halogenation reaction of a hydroxy group.
Among the compounds (V), a compound wherein R ⁵ H H and Y ² is a halogen atom can be produced by subjecting the compound (II) to a Vilsmeier-Haack reaction. As reagents used for the Vilsmeier-Haack reaction, in addition to the above-exemplified reagents, phosphoryl fluoride, phosphoryl bromide, phosphoryl iodide, phosphorus trifluoride, phosphorus trichloride, phosphorus tribromide, phosphorus triiodide, etc. It can be mentioned.
Compound (Ia) can be produced by isothiazole ring formation reaction (1) of compound (V). Examples of reagents used for the isothiazole ring formation reaction (1) include ammonium thiocyanate, sodium thiocyanate and urea, sulfur and ammonia and the like.
The compound (Ia) is also produced by the isothiazole ring formation reaction (2) of the compound (VII) via the compound (VII) produced by the nucleophilic substitution reaction of the compound (V) and the compound (VI) Can. The nucleophilic substitution reaction can also be performed in the presence of a base. The isothiazole ring formation reaction (2) can be performed by reacting compound (VII) with ammonia, hydroxyamine or the like. The isothiazole ring formation reaction (2) is to be carried out in the presence of a reagent such as sulfuryl chloride, polyphosphoric acid, diphosphorus pentaoxide, sodium hypochlorite, potassium hypochlorite in addition to the above-mentioned acidic catalyst or base You can also.

[Manufacturing method 2]
Among compounds (I), compound (Ib) in which X is N can also be produced from compound (VIII) by the following production method or a method analogous thereto.

In the formula, P ¹ and P ² each represent a protecting group of the carbonyl group of the ketone, and P ¹ and P ² may form a ring. P ³ represents a good C _6-14 aryl group which is optionally substituted C _1-6 alkyl group or a substituted.
In the formula, Y ⁴ and Y ^{5 each} represent a C _1-6 alkyl group which may be substituted, a C _6-14 aryl group which may be substituted, a C _1-6 alkoxy group which may be substituted, or a substituent It shows an amino group which may be substituted.
In the formulae, Y ⁶ represents the aforementioned leaving group.
In the formula, Y ⁷ represents the above-mentioned leaving group or M ³ -S-.
In the formula, M ² and the aforementioned M ³ represent a hydrogen atom or an alkali metal atom (eg, lithium atom, sodium atom, potassium atom, rubidium atom, cesium atom, francium atom).
In the formula, R ^{1 ′} represents an ester group which may be substituted, an amido group which may be substituted, a ketone group which may be substituted, an aldehyde group, a carboxyl group, a cyano group or a nitro group.
Other symbols are as defined above.

Compound (VIII) can be commercially available, or can be produced by a method known per se, or a method analogous thereto.
The compound (XIa) or the compound (XIb) is reacted with the compound (IX) in which the carbonyl group of the compound (VIII) is protected, using the compound (Xa) or the compound (Xb) to form a cyclohexylidene hydrazine, respectively. It can be manufactured. The cyclohexylidene hydrazine forming reaction can also be carried out in the presence of a base.
Compound (XII), compound (XIII), or a mixture thereof can be produced by a thiadiazole ring formation reaction of compound (XIa) or compound (XIb). The thiadiazole ring formation reaction can be carried out using a sulfonylating reagent (eg, thionyl chloride etc.) and the like.
Compound (XV) can be produced by the addition reaction of carbon disulfide of compound (XIII). The addition reaction of carbon disulfide can be carried out using carbon disulfide and compound (XIV), and can also be carried out in the presence of a base.
Compound (XVII) can be produced by the thiophene ring formation reaction of compound (XV) and compound (XVI). The thiophene ring formation reaction can also be carried out in the presence of a base.
Compound (Ib) is produced by aromatic nucleophilic substitution reaction of compound (XVIII) and compound (XIX). The aromatic nucleophilic substitution reaction can also be performed in the presence of a base.

[Manufacturing method 3]
Compound (Ic) in which R ^3b and R ^4b together form a double bond can also be produced by subjecting compound (Ia) described in Production Method 1 to an oxidation reaction. The oxidation reaction can be performed using the above-described reagent or the like.

Producing another compound belonging to compound (I) by further subjecting the substituent of compound (Ia), compound (Ib) or compound (Ic) prepared by the method described above to a transformation reaction known per se. You can also.
For example, among compound (Ia), compound (Ib), and compound (Ic), a C _1-6 alkyl group in which L is —SO— or —SO ₂ —, and R ² may be substituted, Alternatively, another compound (I) can also be produced by subjecting a compound such as a C _6-14 aryl group which may be substituted or the like to an aromatic nucleophilic substitution reaction using any nucleophile. .
Also, for example, among the compound (Ia), the compound (Ib) and the compound (Ic), L 2 is a bond and R ² is added to the leaving group described above, and a boric acid group, a boric acid ester group, a nitrile group A carbamate group which may be substituted, a carbonate group which may be substituted, an aminosulfonyloxy group which may be substituted, a C _1-6 alkyl-carbonyloxy group which may be substituted, The compound (I) is obtained by subjecting a compound which is also a C _6-14 aryl-carbonyloxy group, an _optionally substituted C _6-14 aryl-phosphate group, etc. to a coupling reaction known per se. It is also possible to produce other compounds belonging to The coupling reaction includes Suzuki coupling, Stille coupling, Buchwald coupling, Negishi coupling, Heck reaction and the like. Reagents such as metal catalysts, phosphine ligands, and bases used in the coupling reaction are added to the above-mentioned reagents and known per se methods [eg, JF Hartwig, S. Shekhar, Q. Shen, F. Barrios- . Landeros, in The Chemistry of Anilines , Z. Rappoport, Ed, Wiley-Intersicence, New York (2007);. L. Jiang, SL Buchwald, in Metal-Catalyzed Cross-Coupling Reactions, 2 nd Ed, A. de Meijere JF Hartwig, in Handbook of Organopalladium Chemistry for Organic Synthesis, A. de Meijere, F. Diederich, Eds., Wiley, New York (2002). F. Diederich, Eds., Wiley-VCH, Weinheim, Germany (2004); JF Hartwig, in Modern Amination Methods, A. Ricci, Ed., Wiley-VCH, the method described in Weinheim, (2000)], or a method analogous thereto.
Furthermore, for example, among compounds (Ia), compounds (Ib), and compounds (Ic), compounds wherein L is -O-, -S-, or -N- and R ² is a hydrogen atom are known per se. Further compounds belonging to compound (I) can be produced by subjecting them to an alkylation reaction of ## STR6 ## an aromatic nucleophilic substitution reaction known per se, an acylation reaction known per se or a coupling reaction known per se. The coupling reactions known per se include those described above.

  Depending on the type of substituent of the starting compound, starting compounds having different substituents can be prepared by applying a method known per se, using the compound produced by the above-mentioned production method as the starting material.

  Compound (I), which is a product of this reaction, may be produced as a single compound or as a mixture.

  When compound (I) has one or more isomers such as optical isomers, stereoisomers, regioisomers, rotational isomers and the like, either one isomer or a mixture is also encompassed in compound (I).

  For example, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I). These isomers can be obtained individually as synthetic products and separation techniques (eg, concentration, solvent extraction, column chromatography, recrystallization) known per se.

  In addition, when a stereoisomer exists in the compound (I), the case where the isomer is single or a mixture thereof is also included in the present invention.

  Compound (I) may be a crystal, and a single crystal or a mixture of crystal forms is encompassed in compound (I). The crystals can be produced by crystallization using a crystallization method known per se.

  Compound (I) may also be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, co-crystals or co-crystal salts are composed of two or more unique substances at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity and stability) Means crystalline material. The co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se.

Examples of the co-crystal or co-crystal salt counter molecule in the compound (I) include acids (for example, carboxylic acids, phosphoric acids, sugar acids, and sulfonic acids), amides, ureas, bases, maltols, amino acids and the like.
Preferred examples of the above carboxylic acids include fumaric acid, citric acid, glutaric acid, malonic acid, succinic acid, maleic acid, malic acid, malic acid, tartaric acid, mandelic acid, lactic acid, gluconic acid, acetic acid, benzoic acid, gentisic acid, salicylic acid And horse uric acid.
As a suitable example of the said sugar acid, ascorbic acid is mentioned.
Preferred examples of the sulfonic acid include 2-naphthalenesulfonic acid, 10-camphorsulfonic acid and methanesulfonic acid.
Preferred examples of the above-mentioned amide include nicotinamide, benzamide, lactamide, glycolamide, saccharin.
Preferred examples of the above bases include tromethamine and meglumine.
Preferred examples of the maltol include ethyl maltol.
Preferred examples of the above amino acids are tyrosine, alanine, serine, threonine, isoleucine, leucine, arginine, lysine, lysine, proline, tryptophan, valine, glutamic acid, aspartic acid, glycine, asparagine, methionine, cysteine, phenylalanine, glutamine, histidine It can be mentioned.

  Compound (I) may be a hydrate, non-hydrate, solvate or non-solvate.

The compound (I) may be labeled with an isotope (eg, ² H, ³ H, ¹¹ C, ¹⁴ C, ³⁵ S, ¹²⁵ I) or the like, and the compound (I) labeled or substituted with the isotope For example, it can be used as a tracer (PET tracer) used in positron emission tomography (Positron Emission Tomography: PET), and is useful in the field such as medical diagnosis.

Compound (I) may be a prodrug.
The prodrug of compound (I) is a compound which is converted to compound (I) by reaction with an enzyme or gastric acid under physiological conditions in the living body, that is, enzymatic oxidation, reduction, hydrolysis etc. Or a compound which is converted to a compound (I) by hydrolysis or the like by gastric acid or the like. Examples of prodrugs of compound (I) include compounds wherein the amino of compound (I) is acylated, alkylated or phosphorylated (eg, amino of compound (I) is eicosanoylated, analylated, pentylaminocarbonylated , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidinyl methylation, pivaloyloxymethylation, tert-butylated compounds); Compound (I) hydroxy is acylated, alkylated, phosphorylated, boronated compound (eg, compound (I) hydroxy is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl Dimethylaminomethylcarbonylated compounds) compounds in which the carboxy of compound (I) is esterified and amidated (examples Compound (I) carboxy-ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl ester (2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyl oxycarbonylethyl esterification, methyl amidated compounds). These compounds can be produced from compound (I) by a method known per se.
In addition, prodrugs of Compound (I) are those which change into Compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Pharmaceuticals,” Volume 7, Molecular Design, pages 163 to 198. It may be.

Compound (I) or a prodrug thereof (which may be abbreviated as “the compound of the present invention” herein) has CDK8 and / or CDK19 inhibitory activity, and is a clinically useful prophylactic or therapeutic agent for cancer, It is useful as a cancer growth inhibitor, cancer metastasis inhibitor, apoptosis promoter and the like.
The compounds of the present invention can also be used for the prevention or treatment of CDK8- and / or CDK19-related diseases in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans).
The compound of the present invention is excellent in membrane permeability and can be used to obtain medicinal effects at a low dose, and therefore, it is an excellent preventive / therapeutic agent for cancer etc. with reduced side effects. The compound of the present invention exhibits pharmacological effects, pharmacokinetics (eg, absorption, distribution, metabolism, excretion), solubility (eg, water solubility), interaction with other pharmaceutical agents (eg, drug metabolizing enzyme inhibitory action), safety It is also excellent in sexuality (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central toxicity) and stability (eg, chemical stability, stability to enzymes). It is useful as a medicine.

The cancer to which the compound of the present invention is applied is, for example, colon cancer (eg, colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (eg, Non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (eg, pancreatic duct cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (eg, papillary adenocarcinoma, mucus) Sexual adenocarcinoma, adenosquamous cell carcinoma, duodenal cancer, small intestine cancer, breast cancer (eg, invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), ovarian carcinoma (eg, epithelial ovarian carcinoma, extragonadal embryo) Cell tumor, ovarian germ cell tumor, low-grade ovarian cancer), testicular cancer, prostate cancer (eg, hormone-dependent prostate cancer, hormone-independent prostate cancer, castration-resistant prostate cancer), liver cancer (eg, Hepatocellular carcinoma, primary liver cancer, extrahepatic cholangiocarcinoma), thyroid carcinoma (eg, medullary thyroid carcinoma), kidney cancer (eg, renal cell carcinoma, renal pelvis) Transitional cell carcinoma of the ureter), uterine cancer (eg, endometrial cancer, cervical cancer, endometrial cancer, uterine sarcoma), gestational choriocarcinoma, brain tumor (eg, medulloblastoma, glioma, pine) Terminal stellate tumor, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (eg, basal cell carcinoma, malignant melanoma) , Sarcoma (eg, rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma), malignant bone tumor, bladder cancer, hematologic cancer (eg, multiple myeloma, leukemia (eg, acute myeloid leukemia), malignant) Lymphoma, Hodgkin's disease, chronic myeloproliferative disease), cancer of unknown primary site.
Among others, the compound of the present invention is effective against colon cancer, pancreatic cancer, prostate cancer, sarcoma, and blood cancer (eg, multiple myeloma, leukemia (eg, acute myeloid leukemia)).

The compounds of the present invention can be orally or parenterally administered to mammals (preferably humans) as medicaments, as they are or in combination with pharmacologically acceptable carriers.
Hereinafter, the medicament comprising the compound of the present invention (sometimes abbreviated as "the medicament of the present invention") will be described in detail. The dosage form of the medicament of the present invention includes, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, intraoral rapid disintegrating tablets), pills, granules, powders, capsules (soft capsules, Oral agents such as microcapsules), syrups, emulsions, suspensions, films (eg, orally disintegrating films, oral mucous membrane adhesive films) and the like can be mentioned. Moreover, as a dosage form of the medicine of the present invention, for example, injections, drips, transdermal agents (eg, iontophoretic transdermal agents), suppositories, ointments, transnasal agents, transpulmonary agents, eye drops And the like. In addition, the medicament of the present invention may be a controlled release preparation such as an immediate release preparation or a sustained release preparation (including a sustained release microcapsule).

The medicament of the present invention can be produced by a known production method (for example, the method described in the Japanese Pharmacopoeia) generally used in the field of pharmaceutical technology. In the pharmaceutical of the present invention, if necessary, excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, colorants which are usually used in the pharmaceutical field. Additives such as preservatives, fragrances, flavors, stabilizers, thickeners and the like can be suitably contained in appropriate amounts.
The above-mentioned pharmacologically acceptable carrier includes these additives.

  For example, tablets can be manufactured using excipients, binders, disintegrants, lubricants, etc., and pills and granules can be manufactured using excipients, binders, disintegrants. Can. In addition, powders and capsules can be manufactured with excipients and the like, syrups with a sweetener and the like, emulsions and suspensions with a suspending agent, surfactant, emulsifier and the like.

Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium hydrogen carbonate, calcium phosphate and calcium sulfate.
Examples of binders include 5 to 10 wt% starch paste solution, 10 to 20 wt% gum arabic solution or gelatin solution, 1 to 5 wt% tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, glycerin.
Examples of disintegrants include starch and calcium carbonate.
Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, and purified talc.
Examples of sweetening agents include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin and simple syrup.
Examples of surfactants include sodium lauryl sulfate, polysorbate 80, sorbitan mono fatty acid ester, polyoxyl 40 stearate.
Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, bentonite.
Examples of emulsifying agents include gum arabic, tragacanth, gelatin, polysorbate 80.

  For example, when the medicament of the present invention is a tablet, the tablet is added to the compound of the present invention according to a method known per se, for example, excipients (eg, lactose, sucrose, starch), disintegrants (eg, starch, carbonated Calcium), binders (eg starch, gum arabic, carboxymethylcellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose) or lubricants (eg talc, magnesium stearate, polyethylene glycol 6000) and compression molded, then necessary Thus, they can be produced by coating in a manner known per se for the purpose of masking the taste, enteric or persistence. As a coating agent used for coating, for example, hydroxypropyl methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F 68, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg, bengala, titanium dioxide) are used.

  The injections include, in addition to intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, drip injections and the like.

  Such injections are prepared in a manner known per se, that is, by dissolving, suspending or emulsifying the compound of the present invention in a sterile aqueous or oily liquid. Examples of the aqueous liquid include physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride) and the like. The aqueous liquid contains a suitable solubilizer such as alcohol (eg ethanol), polyalcohol (eg propylene glycol, polyethylene glycol), nonionic surfactant (eg polysorbate 80, HCO-50). It may be Examples of the oily liquid include sesame oil, soybean oil and the like. The oily liquid may contain suitable solubilizers. Examples of the solubilizer include benzyl benzoate, benzyl alcohol and the like. In addition, the injections include buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride), stabilizers (eg, human serum albumin, polyethylene glycol) And preservatives (eg, benzyl alcohol, phenol) may be blended. The prepared injection is usually filled in an ampoule.

  Although the content of the compound of the present invention in the medicament of the present invention varies depending on the form of the preparation, it is usually about 0.01 to about 100% by weight, preferably about 2 to about 85% by weight based on the whole preparation. More preferably, it is about 5 to about 70% by weight.

  The content of the additive in the medicament of the present invention varies depending on the form of the preparation, but it is usually about 1 to about 99.9% by weight, preferably about 10 to about 90% by weight based on the whole preparation. is there.

  The compounds of the present invention can be used stably, with low toxicity and safely. The daily dose of the compound of the present invention varies depending on the patient's condition, body weight, type of compound, administration route, etc. For example, when orally administered to a patient for the purpose of treating cancer, adults (body weight about 60 kg) 1 The daily dose of the compound of the present invention is about 1 to about 1000 mg, preferably about 3 to about 300 mg, more preferably about 10 to about 200 mg, which is administered once or in 2 or 3 times. Can.

  When the compound of the present invention is administered parenterally, it is usually administered in the form of a solution (eg, injection). Although the single dose of the compound of the present invention varies depending on the administration subject, target organ, condition, administration method, etc., it is usually about 0.01 to about 100 mg, preferably about 0.01 to about 50 mg per kg body weight. More preferably, about 0.01 to about 20 mg of the compound of the present invention is administered by intravenous injection.

  The compounds of the present invention can be used in combination with other drugs. Specifically, the compounds of the present invention can be used in combination with drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or cell growth factors and agents that inhibit the action of their receptors. Hereinafter, drugs that can be used in combination with the compound of the present invention are abbreviated as concomitant drugs.

  Examples of “hormone therapeutic agents” include phosphestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepaltricin, Raloxifene, olmeloxifene, levormeloxifene, anti-estrogen (eg, tamoxifen citrate, toremifene citrate), pill formulation, mepithiostan, testolactone, aminoglutethiimide, LH-RH agonist (eg, goserelin acetate, buserelin (Leuprorelin acetate), droloxifene, epithiostanol, ethynyl estradiol sulfonate, aromatase inhibitors (eg, fadrozole hydrochloride, anastrozole, leto Zole, exemestane, vorozole, formestane), antiandrogens (eg, flutamide, bicalutamide, nilutamide), 5α-reductase inhibitors (eg, finasteride, epristeride), corticosteroids (eg, dexamethasone, prednisolone, betamethasone, triamcinolone) And inhibitors of androgen synthesis (eg, abiraterone), drugs that retard retinoid and retinoid metabolism (eg, liarozole), thyroid hormones, and their DDS (Drug Delivery System) formulations.

  As the "chemotherapeutic agent", for example, alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents are used.

  Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carbocon, inprosulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, mel Phalaen, dacarbazine, lanimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etolequiside, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, alretamine, ambamustin, dibrospidium hydrochloride, fotemustine, Prednismustine, pumithepa, ribomustine, temozolomide, treosulphan, trofosfamide, Roh statins scan chima Lamar, adozelesin, cystemustine, Bizereshin and DDS preparations thereof are used.

  Examples of the "metabolite" include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, pecitrexide, enocitabine, cytarabine, cytarabine ocfosphato, ancitabine hydrochloride, 5-FU drug (eg, fluorouracil, tegafur, UFT, doxifluridine, carmofur, galocitabine, emitefur, capecitabine), aminopterin, nelzalavin, leucovorin calcium, tabloid, butosin, folinate calcium, levoforinate calcium, cladolibine, emiteful, fludarabine, gemcitabine, hydroxycarbamide, hydroxy carbamide Idoxyuridine, Mitoguazone, Thiazofrine, Ambamustine, Bendamustine and their D S formulation is used.

  Examples of the "anticancer antibiotic" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride Neocarzinostatin, misuramycin, sarkomycin, carcininophilin, mitotane, zolubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS preparations are used.

  As the “plant-derived anticancer agent”, for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine and their DDS preparations are used.

  Examples of the “immunotherapeutic agent” include picibanil, krestin, sizofiran, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum , Levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody are used.

  The "cell growth factor" in the "cell growth factor and a drug that inhibits the action of its receptor" may be any substance that promotes cell growth, and generally has a molecular weight of 20,000 or less. The peptide includes an agent that exerts an action at a low concentration by binding to a receptor, and specifically, (1) a substance having an EGF (epidermal growth factor) or an activity substantially identical thereto [eg, TGFα], (2) insulin or a substance having substantially the same activity as it (eg, insulin, IGF (insulin-like growth factor) -1, IGF-2), (3) FGF (fibroblast growth factor) or it Substances having substantially the same activity [eg, acidic FGF, basicity GF, KGF (keratinocyte growth factor), FGF-10], (4) other cell growth factors [eg, CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth) factor (PD), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), heregulin, angiopoietin] are used.

  The “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor, and specifically, an EGF receptor, heregulin receptor (eg, HER3) ), Insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (eg, Tie2), PDGF receptor, etc. .

  Examples of “a drug that inhibits the action of a cell growth factor and its receptor” include an EGF inhibitor, a TGFα inhibitor, a haregulin inhibitor, an insulin inhibitor, an IGF inhibitor, an FGF inhibitor, a KGF inhibitor, a CSF inhibitor, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGFβ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, insulin receptor Body inhibitor, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibition Agent, VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, Src inhibitor, PKC inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1 / 2) inhibitor, MET inhibitor, CDK inhibitor, Akt inhibitor, ERK Inhibitors and the like are used. More specifically, anti-VEGF antibody (eg, Bevacizumab), anti-HER2 antibody (eg, Trastuzumab, Pertuzumab), anti-EGFR antibody (eg, Cetuximab, Panitumumab, Matuzumab, Nimotuzumab), anti-VEGFR antibody, anti-HGF antibody, Imatinib mesylate, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, 4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-7- [3- (1-pyrrolidinyl) Propoxy] quinazoline (AZD-2171), Lestaurtinib, Pazopanib, Canertin b, Tandutinib, 3- (4-bromo-2,6-difluorobenzyloxy) -5- [3- [4- (1-pyrrolidinyl) butyl] ureido] isothiazole-4-carboxamide (CP-547632), Axitinib N- (3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl) -2- (pyridin-4-ylmethylamino) pyridine-3-carboxamide (AMG-706), Nilotinib, 6 -[4- (4-ethylpiperazin-1-ylmethyl) phenyl] -N- [1 (R) -phenylethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (AEE-788), Vandetanib, Temsirolimus, Everolimus, Enzastaurin, N- [4- [4- (4 (4) -Methylpiperazin-1-yl) -6- (3-methyl-1H-pyrazol-5-ylamino) pyrimidin-2-ylsulfanyl] phenyl] cyclopropanecarboxamide (VX-680), phosphoric acid 2- [N- [N- [ 3- [4- [5- [N- (3-Fluorophenyl) carbamoylmethyl] -1H-pyrazol-3-ylamino] quinazoline-7-yloxy] propyl] -N-ethylamino] ethyl ester (AZD-1152) , 4- [9-chloro-7- (2,6-difluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-ylamino] benzoic acid, N- [2-methoxy-5-, [(E) -2- (2,4,6-Trimethoxyphenyl) vinylsulfonylmethyl] phenyl] glycine sodium salt (ON-1910 a), 4- [8-Cyclopentyl-7 (R) -ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino] -3-methoxy-N- (1-) Methylpiperidin-4-yl) benzamide (BI-2536), 5- (4-bromo-2-chlorophenylamino) -4-fluoro-1-methyl-1H-benzimidazole-6-carbohydroxamic acid 2-hydroxyethyl ester (AZD-6244), N- [2 (R), 3-dihydroxypropoxy] -3,4-difluoro-2- (2-fluoro-4-iodophenylamino) benzamide (PD-0325901), everolimus (RAD001) Etc. are used.

  In addition to the above drugs, L-asparaginase, acegraton, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercury hematoporphyrin sodium, topoisomerase I inhibitors (eg, irinotecan, topotecan), topoisomerase II inhibitors (eg, sobuzoxane), Differentiation-inducing agents (eg, retinoids, vitamin Ds), other angiogenesis inhibitors (eg, fumagillin, shark extract, COX-2 inhibitors), α-blockers (eg, tamsulosin hydrochloride), bisphosphonic acids (eg, Antitumor antibodies such as pamidronate, zoledronate), thalidomide, 5azacytidine, decitabine, proteasome inhibitors (eg, bortezomib), anti-CD20 antibodies, toxin-labeled antibodies, etc. can also be used as concomitant drugs.

  By combining the compound of the present invention and the concomitant drug, (1) the dosage can be reduced as compared with the case where the compound of the present invention or the concomitant drug is administered alone; Depending on the severity etc.), the drug to be used in combination with the compound of the present invention can be selected, (3) the treatment period can be set long, (4) the therapeutic effect can be sustained, (5) By using the compound of the present invention and the concomitant drug in combination, excellent effects such as a synergistic effect can be obtained.

Hereinafter, the case where the compound of the present invention and the concomitant drug are used in combination is referred to as "the concomitant drug of the present invention".
When using the concomitant drug of the present invention, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be simultaneously administered to the subject of administration. It may be administered. When administering with a time lag, the time lag varies depending on the active ingredient, dosage form, and administration method to be administered, but for example, when the concomitant drug is administered first, within 1 minute to 3 days after administering the concomitant drug, preferably The compound of the present invention may be administered within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, the concomitant drug may be administered within 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour after administering the compound of the present invention . The dose of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.

Examples of administration forms in which the compound of the present invention and the concomitant drug are used in combination include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) combined use with the compound of the present invention Simultaneous administration by the same route of administration of two preparations obtained by separately formulating the drug and (3) by the same route of administration of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug Administration with time lag, (4) coadministration of two formulations obtained by separately formulating the compound of the present invention and the concomitant drug in different administration routes, and (5) the compound of the present invention and the concomitant drug Administration with different administration routes by two administrations obtained by separately formulating with different administration routes (for example, administration in the order of the compound of the present invention → combination drug or administration in the reverse order) can be mentioned.
The dose of the concomitant drug can be appropriately selected based on the dose clinically used. The compounding ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, condition, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used based on 1 part by weight of the compound of the present invention.

Furthermore, the compound of the present invention or the combination drug of the present invention can be used in combination with non-drug therapy.
Specifically, the compound of the present invention or the combination drug of the present invention includes, for example, (1) surgery, (2) hypertensive chemotherapy using angiotensin II or the like, (3) gene therapy, (4) thermotherapy, (5) It can also be combined with cryotherapy, (6) laser ablation, (7) nondrug therapy of radiation therapy.

  For example, use of the compound of the present invention or the combination drug of the present invention before or after the aforementioned surgery or the like, or before or after the treatment combining these two or three types, inhibition of development of tolerance, disease free (Disease-Free Survival) Effects such as prolonging), suppressing cancer metastasis or recurrence, and prolonging life.

  In addition, therapy with the compound of the present invention or the concomitant drug of the present invention, and supportive therapy [(i) an antibiotic against co-occurrence of various infectious diseases (eg, β-lactams such as pansporin, macrolides such as clarithromycin)] Administration, (ii) hypercaloric infusion to improve malnutrition, amino acid preparation, administration of multivitamins, (iii) morphine administration for pain relief, (iv) nausea, vomiting, anorexia, diarrhea, leukopenia, Administration of a drug that improves side effects such as thrombocytopenia, hemoglobin concentration reduction, alopecia, liver disorder, renal disorder, DIC, fever, etc., and (v) administration of a drug for suppressing multidrug resistance of cancer etc. It can also be done.

  The present invention is further described in detail by the following examples, formulation examples and test examples, but these are not intended to limit the present invention, and may be changed within the scope of the present invention.

  In the following examples, "room temperature" usually indicates about 10 ° C to about 35 ° C. The ratio shown in the mixed solvent indicates the volume ratio unless otherwise specified. % Indicates weight% unless otherwise specified.

  When it was described as NH 2 in silica gel column chromatography, aminopropylsilane-bonded silica gel was used. When described as C18 in HPLC (high performance liquid chromatography), octadecyl-bonded silica gel was used. The ratio of elution solvents indicates the volume ratio unless otherwise specified.

The following abbreviations are used in the following examples and test examples.
mp: melting point
MS: Mass spectrum
M: molar concentration
CDCl ₃ : Heavy chloroform
DMSO-d ₆ : Heavy dimethyl sulfoxide
¹ H NMR: proton nuclear magnetic resonance
LC / MS: Liquid chromatograph mass spectrometer
HPLC: high performance liquid chromatography
ESI: Electrospray ionization
APCI: Atmospheric pressure chemical ionization
DBU: 1,8-Diazabicyclo [5.4.0] -7-undecene
DCM: dichloromethane
DIEA: N-ethyl-N-isopropylpropan-2-amine
DMA: N, N-Dimethylacetamide
DMAP: N, N-dimethyl-4-aminopyridine
DME: 1,2-dimethoxyethane
DMF: N, N-dimethylformamide
DMSO: dimethyl sulfoxide
DPPF: 1,1'-bis (diphenylphosphino) ferrocene
mCPBA: m-chloroperbenzoic acid
HATU: o- (7-Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
HOBt: 1-hydroxybenzotriazole
NMP: 1-methylpyrrolidin-2-one
THF: tetrahydrofuran
TFA: trifluoroacetic acid
TFAA: anhydrous trifluoroacetic acid
Pd ₂ (dba) ₃ : Tris (dibenzylideneacetone) dipalladium (0)
WSC: N- (3- (dimethylamino) propyl) -N'-ethylcarbodiimide
WSCD: N- (3- (Dimethylamino) propyl) -N'-ethylcarbodiimide hydrochloride
X-Phos: dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine

¹ H NMR was measured by Fourier transform NMR. For analysis, ACD / SpecManager (trade name) etc. were used. There is no description about a very mild peak such as a hydroxyl group or an amino group.
MS was measured by LC / MS. As the ionization method, ESI method or APCI method was used. Data described actual value (found). Usually, the molecular ion peak ^{([M + H] +,} [MH] - , etc.) is observed, for example, in the case of compounds having a tert- butoxycarbonyl group, as a fragment ion, tert- butoxycarbonyl group or a tert A peak from which a -butyl group is eliminated is observed, and in the case of a compound having a hydroxyl group, a peak from which H ₂ O is eliminated as a fragment ion may be observed. In the case of a salt, a free molecular ion peak or fragment ion peak is usually observed.
The unit of sample concentration (c) in optical rotation ([α] _D ) is g / 100 mL.
Elemental analysis values (Anal.) Were calculated (Calcd) and actual value (Found).

Example 1
8- (4-Bromophenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) Ethyl 3- (methylsulfanyl) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate cyclohexane-1,3-dione (38.9 g) and DMF (300 mL) Potassium carbonate (125 g) was added to the mixture of at room temperature and stirred at the same temperature for 10 minutes. Carbon disulfide (22.1 mL) was added to the reaction mixture and stirred at room temperature for 15 minutes. A mixture of ethyl chloroacetate (37.5 g) and DMF (300 mL) was added dropwise to the reaction mixture at 40 ° C. or less over 2 hours, and the mixture was stirred at room temperature for 20 minutes. After ice-cooling the reaction mixture, iodomethane (20.6 mL) was added dropwise over 10 minutes at 10 ° C. or less. The reaction mixture was stirred at 50 ° C. for 4 hours and then cooled to room temperature. Water (1.5 L) was added dropwise to the reaction mixture at 20 ° C. or less over 45 minutes, and then stirred overnight at room temperature. The precipitate was collected by filtration, washed with water and dried at 60 ° C. for 1 day to give the title compound (63.0 g).
MS: [M + H] ^< +> 270.8.

(A ') Ethyl 3- (methylsulfanyl) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate cyclohexane-1,3-dione (64. 9 g) and DMF (500 To the mixture of mL) potassium carbonate (208 g) was added at room temperature and stirred for 10 minutes at the same temperature. Carbon disulfide (46.6 g) was added to the reaction mixture and stirred at room temperature for 15 minutes. A mixture of ethyl chloroacetate (62.5 g) and DMF (500 mL) was added dropwise to the reaction mixture at 40 ° C. or less over 1.5 hours, and the mixture was stirred at room temperature for 20 minutes. After ice-cooling the reaction mixture, iodomethane (78.4 g) was added dropwise over 10 minutes at 10 ° C. or less. The reaction mixture was stirred at 50-54 ° C. for 4 hours and then cooled to room temperature. Water (2.5 L) was added dropwise to the reaction mixture at 20 ° C. or lower over 45 minutes, and then stirred overnight at room temperature. The precipitate was collected by filtration, washed with water and dried under reduced pressure at 60 ° C. for 5 hours to give the title compound (101 g).
MS: [M + H] ⁺ 271.1.

(B) Ethyl 3- (methylsulfonyl) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 3- (methylsulfanyl) -4-oxo-4,5 69-75% mCPBA (48.6 g) was added to a mixture of 6,7-tetrahydro-2-benzothiophene-1-carboxylate (21.3 g) and DMF (220 mL) under ice-cooling, and then at room temperature for 48 hours The mixture was stirred at 40 ° C. for 16 hours. Water (1 L) was added to the reaction mixture at room temperature, and the precipitate was collected by filtration, and then washed with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium thiosulfate solution, and water to give the title compound (21.3 g).
MS: [M + H] ^< +> 302.9.

(B ') Ethyl 3- (methylsulfonyl) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 3- (methylsulfanyl) -4-oxo-4,5 , 6,7-Tetrahydro-2-benzothiophene-1-carboxylate (97.2 g) and ethanol (1.0 L) / water (1.0 L) in a mixture of potassium peroxymonosulfate sulfate (729 g) at 60-64 ° C The mixture was added dropwise over 40 minutes and then stirred at the same temperature for 17 hours. Water (2.0 L) was added dropwise to the reaction mixture at 50-64 ° C. over 30 minutes. The mixture was cooled to 15 ° C. using an ice-cold water bath, the precipitate was separated by filtration, washed with water (7.0 L) and dried at 60 ° C. under reduced pressure for 5 hours to give the title compound (98.0 g).
MS: [M + H] ⁺ 303.1.

(C) Ethyl 3- (4-bromophenoxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 3- (methylsulfonyl) -4-oxo-4, 4-Bromophenol (6.34 g) and potassium carbonate (6.80 g) in a mixture of 5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (9.87 g) and ethyl acetate (80 mL) / toluene (80 mL) After adding g) at room temperature, the reaction mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was added to water (200 mL) at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (11.4 g).
MS: [M + H] ^< +> 394.9.

(D) Ethyl 8- (4-bromophenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate In ice-cold DMF (100 mL) phosphite tribromide After adding (6.0 mL) dropwise, the mixture was stirred at 80 ° C. for 30 minutes. To the reaction mixture was added a mixture of ethyl 3- (4-bromophenoxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (11.4 g) and DMF (50 mL) After stirring, it was stirred at 80.degree. C. for 1 hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. After adding ammonium thiocyanate (6.71 g) to a mixture of the residue and acetone (120 mL) at room temperature, the mixture was stirred at 55 ° C. for 1 hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and then recrystallized from ethyl acetate / hexane to give the title compound (3.38 g).
MS: [M + H] ^< +> 435.8.

(E) 8- (4-Bromophenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid ethyl 8- (4-bromophenoxy) -4,5- 8 N aqueous solution of sodium hydroxide (3.39 mL) in a mixture of dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (2.37 g) and THF (20 mL) / methanol (20 mL) Was added at room temperature and stirred at the same temperature for 4 hours. To the reaction mixture were added 6 N aqueous hydrochloric acid solution (4.30 mL) and saturated aqueous ammonium chloride solution (100 mL) at room temperature, and then extracted with a mixture of ethyl acetate / THF. The aqueous layer was extracted with ethyl acetate, the extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (2.17 g).
MS: [M + H] ^< +> 407.8.

(F) 8- (4-bromophenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
HOBt (389 mg) in a mixture of 8- (4-bromophenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (759 mg) and DMF (10 mL) ), WSC (494 μL), DIEA (986 μL), and ammonium chloride (500 mg) were added at room temperature and stirred overnight at the same temperature. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate / heptane to give the title compound (598 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 2.98-3.09 (2H, m), 3.30-3.40 (2H, m), 5.61 (2H, brs), 7.05-7.16 (2H, m), 7.47-7.58 (2H , m), 8.33 (1 H, s).

Example 2
8- (4-Cyanophenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8- (4-Bromophenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (100 mg), NMP (1.5 mL), and copper (I) cyanide The mixture of (34 mg) was stirred under microwave irradiation at 180 ° C. for 2 hours. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate / hexane) and then separated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)), and the obtained fraction is saturated with carbonic acid Aqueous sodium hydrogen solution was added and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound (5.9 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.94-3.02 (2H, m), 3.22-3.29 (2H, m), 7.39-7.47 (2H, m), 7.58 (2H, s), 7.91-7.98 (2H, m), 8.50 (1 H, s).

Example 3
8- (4- (morpholin-4-ylcarbonyl) phenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8- (4-Bromophenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (100 mg), trans-bis (acetato) bis [o- (di- o-Tolylphosphino) benzyl] dipalladium (II) (24 mg), tri (tert-butylphosphonium) tetrafluoroborate (15 mg), hexacarbonylmolybdenum (68 mg), morpholine (44 μL), DBU (424 μL ) And THF (3 mL) were stirred at 125 ° C. for 1 hour under microwave irradiation. The reaction mixture was added to a mixture of ethyl acetate / THF / water. The organic layer was separated, washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and then recrystallized from ethyl acetate / heptane to give the title compound (17 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.94-3.02 (2H, m), 3.21-3.29 (2H, m), 3.38-3.70 (8H, m), 7.30-7.39 (2H, m), 7.48 -7.58 (4H, m), 8.50 (1 H, s).

Example 4
8- (4- (Dimethylcarbamoyl) phenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) Ethyl 8- (4- (dimethylcarbamoyl) phenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate
8- (4-Bromophenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (300 mg), trans-bis (acetato) bis [o- (di- o-Tolylphosphino) benzyl] dipalladium (II) (67 mg), tri (tert-butylphosphonium) tetrafluoroborate (41 mg), hexacarbonylmolybdenum (189 mg), 2.0 M dimethylamine in THF (688 μL) ), DBU (1.19 mL), and a mixture of THF (3 mL) were stirred at 125 ° C. for 1 hour under microwave irradiation. The reaction mixture was added to a mixture of ethyl acetate / water. The organic layer was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane and NH, ethyl acetate / hexane) to give the title compound (125 mg).
MS: [M + H] ^< +> 428.9.

(B) 8- (4- (Dimethylcarbamoyl) phenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamidoethyl 8- (4- (dimethylcarbamoyl) phenoxy) 2 N sodium hydroxide in a mixture of -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (110 mg) and THF (8 mL) / methanol (8 mL) The aqueous solution (642 μL) was added and stirred at room temperature for 5 hours. To the reaction mixture were added 2 N aqueous hydrochloric acid (610 μL) and saturated aqueous ammonium chloride (50 mL) at room temperature, and the mixture was extracted with a mixture of ethyl acetate / THF. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. To a mixture of the residue and DMF (5 mL), HOBt (52 mg), WSC (68 μL), DIEA (136 μL), and ammonium chloride (69.0 mg) were added at room temperature and stirred overnight at the same temperature. The reaction mixture was added to water at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / heptane to give the title compound (39 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.87-3.05 (8H, m), 3.21-3.29 (2H, m), 7.28-7.37 (2H, m), 7.46-7.56 (4H, m), 8.50 (1H, s).

Example 5
8- (4- (Propylsulfonyl) phenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) 4- (propylsulfanyl) phenol
After 1-bromopropane (401 μL) and potassium carbonate (594 mg) were added to a mixture of 4-sulfanylphenol (500 mg) and acetone (10 mL) at room temperature, the reaction mixture was stirred overnight at room temperature. The reaction mixture was added to water at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (436 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 0.99 (3 H, t, J = 7.3 Hz), 1.60 (2 H, tq, J = 7.3, 7.3 Hz), 2.79 (2 H, t, J = 7.3 Hz), 4.95 (1H, brs), 6.72-6.82 (2H, m), 7.23-7.34 (2H, m).

(B) Ethyl 4-oxo-3- (4- (propylsulfanyl) phenoxy) -4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 3- (methylsulfonyl) -4-oxo 4- (Propylsulfanyl) phenol (306 mg) in a mixture of -4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (500 mg) and ethyl acetate (5 mL) / toluene (5 mL) After the addition of potassium carbonate (345 mg) at room temperature, the reaction mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was added to water at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (508 mg).
MS: [M + H] ^< +> 390.9.

(C) Ethyl 4-oxo-3- (4- (propylsulfonyl) phenoxy) -4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 4-oxo-3- (4- (4- (4 69-75% mCPBA (789 mg) at room temperature in a mixture of propylsulfanyl) phenoxy) -4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (500 mg) and DMF (5 mL) And stirred overnight at the same temperature. The reaction mixture was added to saturated sodium thiosulfate and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (461 mg).
MS: [M + H] ^< +> 422.9.

(D) Ethyl 8- (4- (propylsulfonyl) phenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate
After adding tribromide phosphite (326 μL) to DMF (3 mL) at room temperature, the mixture was stirred at 80 ° C. for 15 minutes. After adding ethyl 4-oxo-3- (4- (propylsulfonyl) phenoxy) -4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (440 mg) to the reaction mixture, the mixture was heated to 80 ° C. The mixture was stirred for 1 hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. After adding ammonium thiocyanate (242 mg) to a mixture of the residue and acetone (10 mL) at room temperature, the mixture was stirred at 55 ° C. for 1 hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (279 mg).
MS: [M + H] ^< +> 463.9.

(E) 8- (4- (Propylsulfonyl) phenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamidoethyl 8- (4- (propylsulfonyl) phenoxy) 2 N sodium hydroxide in a mixture of -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (270 mg) and THF (3 mL) / methanol (3 mL) The aqueous solution (874 μL) was added and stirred at room temperature for 5 hours. To the reaction mixture were added 2 N aqueous hydrochloric acid solution (850 μL) and saturated aqueous ammonium chloride solution (50 mL) at room temperature, and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the residue and DMF (5 mL), HOBt (118 mg), WSC (155 μL), DIEA (309 μL), and ammonium chloride (157 mg) were added at room temperature and stirred overnight at the same temperature. The reaction mixture was added to water at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / heptane to give the title compound (119 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 1.02 (3 H, t, J = 7.5 Hz), 1.68-1.84 (2 H, m), 3.00-3.12 (4 H, m), 3.32-3. 42 (2 H, m), 5.63 (2H, brs), 7.29-7.38 (2H, m), 7.89-7.98 (2H, m), 8.34 (1H, s).

Example 6
8- (4-Cyano-3- (methylsulfonyl) phenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) 4- (benzyloxy) -2-fluorobenzonitrile
After adding (bromomethyl) benzene (963 μL) and potassium carbonate (1.50 g) to a mixture of 2-fluoro-4-hydroxybenzonitrile (1.00 g) and DMF (30 mL) at room temperature, the reaction mixture is heated to the same temperature. Stir overnight. The reaction mixture was added to water at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.21 g).
MS: [M + H] ^< +> 227.9.

(B) 4- (benzyloxy) -2- (methylsulfanyl) benzonitrile
After sodium methanethiolate (325 mg) was added to a mixture of 4- (benzyloxy) -2-fluorobenzonitrile (500 mg) and DMF (10 mL) at room temperature, the reaction mixture was stirred overnight at the same temperature. The reaction mixture was added to saturated aqueous ammonium chloride solution at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (442 mg).
MS: [M + H] ^< +> 255.9.

(C) 4-hydroxy-2- (methylsulfanyl) benzonitrile
After adding chlorotrimethylsilane (653 μL) and sodium iodide (761 mg) to a mixture of 4- (benzyloxy) -2- (methylsulfanyl) benzonitrile (430 mg) and acetonitrile (10 mL) at room temperature The reaction mixture was stirred at room temperature for 3 days under nitrogen atmosphere. The reaction mixture was added to saturated aqueous sodium thiosulfate solution at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (257 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.53 (3 H, s), 6.66 (1 H, dd, J = 8.5, 2.2 Hz), 6.76 (1 H, d, J = 2.2 Hz), 7.58 (1 H, 1 H, d, J = 8.5 Hz), 10.74 (1 H, brs).

(D) Ethyl 3- (4-cyano-3- (methylsulfanyl) phenoxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 3- (methylsulfonyl) 4-hydroxy-2- in a mixture of 4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (399 mg) and ethyl acetate (3 mL) / toluene (3 mL) After (methylsulfanyl) benzonitrile (240 mg) and potassium carbonate (275 mg) were added at room temperature, the reaction mixture was stirred at 80 ° C. for 5 hours. The reaction mixture was added to water at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (317 mg).
MS: [M + H] ^< +> 388.0.

(E) Ethyl 3- (4-cyano-3- (methylsulfonyl) phenoxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 3- (4-cyano -3- (methylsulfanyl) phenoxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (315 mg) in DMF (5 mL), 69-75 % mCPBA (601 mg) was added at room temperature and stirred overnight at the same temperature. The reaction mixture was added to saturated aqueous sodium thiosulfate solution at room temperature and then extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, an aqueous solution and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (221 mg).
MS: [M + H] ^< +> 419.9.

(F) Ethyl 8- (4-cyano-3- (methylsulfonyl) phenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate
After adding tribromide phosphite (157 μL) to DMF (3 mL) at room temperature, the mixture was stirred at 80 ° C. for 15 minutes. The reaction mixture contained ethyl 3- (4-cyano-3- (methylsulfonyl) phenoxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (210 mg) and DMF ( The mixture of 3 mL) was added and stirred at 80 ° C. for 1 hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. After adding ammonium thiocyanate (117 mg) to a mixture of the residue and acetone (10 mL) at room temperature, the mixture was stirred at 55 ° C. for 1 hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (117 mg).
MS: [M + H] ^< +> 460.9.

(G) 8- (4-Cyano-3- (methylsulfonyl) phenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamido ethyl 8- (4-cyano- 3- (Methylsulfonyl) phenoxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (105 mg) with THF (3 mL) / methanol (3 mL) To the mixture, 2 N aqueous sodium hydroxide solution (342 μL) was added, and stirred at room temperature for 5 hours. To the reaction mixture were added 2 N aqueous hydrochloric acid (300 μL) and saturated aqueous ammonium chloride (50 mL) at room temperature, and the mixture was extracted three times with a mixture of ethyl acetate / THF. The extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the residue and DMF (5 mL), HOBt (45 mg), WSC (59 μL), DIEA (118 μL), and ammonium chloride (60 mg) were added at room temperature and stirred overnight at the same temperature. The reaction mixture was added to water at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and then recrystallized from ethyl acetate / heptane to give the title compound (8 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.95-3.04 (2H, m), 3.22-3.30 (2H, m), 3.45 (3H, s), 7.65 (2H, s), 7.75 (1H, dd) , J = 8.6, 2.6 Hz), 7.90 (1 H, d, J = 2.6 Hz), 8.26 (1 H, d, J = 8.6 Hz), 8.52 (1 H, s).

Example 7
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) Ethyl 3-((2-methylpyridin-3-yl) oxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 3- (methylsulfonyl) -4-Oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (2.00 g), 2-methylpyridin-3-ol (0.794 g), potassium carbonate (2.74 g), acetic acid A mixture of ethyl (20 mL) and toluene (20 mL) was stirred at 80 ° C. overnight. The insolubles were filtered off with Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.96 g).
MS: [M + H] ^< +> 331.9.

(B) Ethyl 4-bromo-5-formyl-3-((2-methylpyridin-3-yl) oxy) -6,7-dihydro-2-benzothiophene-1-carboxylate ice cold DMF (25 mL) After adding tribromide (1.7 mL) to nitrogen under a nitrogen atmosphere, the mixture was stirred at 80 ° C. for 10 minutes. The reaction mixture contained ethyl 3-((2-methylpyridin-3-yl) oxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (1.94 g) and DMF After adding 5 mL) at 80 ° C., the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, ice-cold water was added, and basified with saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and extracted with ethyl acetate. The combined extracts were washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (2.20 g) containing the title compound.
MS: [M + H] ^< +> 421.8.

(C) Ethyl 8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate Ethyl 4-bromo-5 -Formyl-3-((2-methylpyridin-3-yl) oxy) -6,7-dihydro-2-benzothiophene-1-carboxylate containing crude product (3.24 g), ammonium thiocyanate (1.75 A mixture of g) and acetone (60 mL) was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was added to saturated aqueous sodium bicarbonate solution, and extracted twice with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (2.08 g).
MS: [M + H] ^< +> 372.9.

(D) Ethyl 8-((2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate 8-((2- Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (85 mg) and THF (2 mL) / ethanol (2 mL) To the mixture was added 2 N aqueous sodium hydroxide solution (1 mL) at room temperature and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and 2 N hydrochloric acid aqueous solution (1 mL) was added. The precipitate was collected by dilution with water and washed with water to give the title compound (76 mg).
MS: [M + H] ^< +> 344.8.

(E) 8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (72 mg) and THF (5 mL) To the mixture was added oxalyl chloride (0.10 mL) and DMF (catalytic amount) at room temperature and stirred at room temperature for 1 hour. The reaction mixture was diluted with toluene and then concentrated under reduced pressure. The residue was diluted with THF (5 mL), 28% aqueous ammonia solution (0.50 mL) was added under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was concentrated under reduced pressure, the residue was added to water, and extracted twice with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate). The obtained product was collected by filtration and washed with ethyl acetate / hexane to give the title compound (57 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.51 (3 H, s), 2.94-3.03 (2 H, m), 3. 20-3. 29 (2 H, m), 7. 35 (1 H, dd, J = 8.2, 4.7 Hz ), 7.46 (2H, s), 7.69 (1 H, dd, J = 8.3, 1.3 Hz), 8.41 (1 H, dd, J = 4.7, 1.3 Hz), 8.51 (1 H, s).

Example 8
8-((2-Methyl-1-oxidopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid
(A) Ethyl 8-((2-methyl-1-oxidopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate Ethyl 8 -((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (300 mg) and DMA (6 mL) / After adding 69-75% mCPBA (306 mg) to a mixture of acetonitrile (12 mL) at room temperature, the mixture was stirred at the same temperature for 1 hour and at 40 ° C. for 28 hours. The reaction mixture was concentrated under reduced pressure, and to the residue were added ethyl acetate and a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with a saturated brine solution and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (270 mg).
MS: [M + H] ^< +> 388.9.

(B) Ethyl 8-((2-methyl-1-oxidopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate ((2-Methyl-1-oxidopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (250 mg) with THF (6.4 To a mixture of (mL) / ethanol (3.2 mL), 2 N aqueous sodium hydroxide solution (1.61 mL) was added at room temperature, and the mixture was stirred at 40 ° C for 14 hours. To the reaction mixture was added 2 N aqueous hydrochloric acid solution (1.6 mL), and the precipitate was separated by filtration to give the title compound (233 mg).
MS: [M + H] ^< +> 360.9.

Example 9
8-((2-Methyl-1-oxidopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) 8-((2-Methyl-1-oxidopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((2-Methyl-1-oxidopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (130 mg) and DMA To the mixture of (12 mL), HOBt (73 mg), WSC (96 μL), DIEA (188 μL), and ammonium chloride (96 mg) were added at room temperature and stirred at 40 ° C. for 60 hours. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The aqueous layer was concentrated, ethyl acetate was added, and the precipitate was filtered off. The extract and the filtrate were combined, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (49 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.42 (3H, s), 2.91-3.05 (2H, m), 3.20-3.29 (2H, m), 7.18-7.28 (1H, m), 7.29-7.38 (1 H, m), 7.53 (2 H, s), 8. 26 (1 H, d, J = 6.3 Hz), 8.52 (1 H, s).

(B) 8-((2-Methyl-1-oxidopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (600 mg) in DMF (6 mL) After adding m-CPBA (70% water-containing product, 646 mg) to the mixture at room temperature, the mixture was stirred at room temperature overnight. To the reaction mixture, m-CPBA (70% water-containing product, 215 mg) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (30 mL), and the precipitate was collected by filtration and washed with ethyl acetate to give a crude product (598 mg). The crude product (550 mg) was recrystallized from 80% ethanol / ethyl acetate to give the title compound (395 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.42 (3H, s), 2.94-3.03 (2H, m), 3.21-3.29 (2H, m), 7.21-7.28 (1H, m), 7.29-7.38 (1 H, m), 7.54 (2 H, s), 8. 26 (1 H, d, J = 6.3 Hz), 8.52 (1 H, s).

Example 10
8-((6-Chloropyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) Ethyl 3-((6-chloropyridin-3-yl) oxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 3- (methylsulfonyl) -4-Oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (500 mg), 6-chloropyridin-3-ol (321 mg), potassium carbonate (686 mg), acetic acid A mixture of ethyl (5 mL) and toluene (5 mL) was stirred at 80 ° C. for 3 hours. The insolubles were filtered off with Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (487 mg).
MS: [M + H] ^< +> 351.8.

(B) Ethyl 8-((6-chloropyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate ice cold DMF (12 After adding tribromide phosphite (0.54 mL) to mL), the mixture was stirred at 80 ° C. for 15 minutes. In the reaction mixture, ethyl 3-((6-chloropyridin-3-yl) oxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (1.00 g) and DMF ( After adding 2 mL) at 80 ° C., the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, ice-cold water was added, and basified with saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and extracted with ethyl acetate. The combined extracts were washed with saturated brine solution and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the residue and acetone (20 mL), ammonium thiocyanate (433 mg) was added and stirred at 60 ° C. for 6 hours. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (764 mg).
MS: [M + H] ^< +> 392.9.

(C) Ethyl 8-((6-chloropyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate 8-((6- Chloropyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (60 mg) and THF (2 mL) / ethanol (2 mL) To the mixture was added 2 N aqueous sodium hydroxide solution (0.5 mL) at room temperature and stirred overnight at room temperature. To the reaction mixture was added 2 N aqueous hydrochloric acid (0.5 mL). The solvent was evaporated under reduced pressure, and the residue was diluted with water, the precipitate was collected by filtration, and washed with water to give the title compound (50 mg).
MS: [M + H] ^< +> 364.8.

(D) 8-((6-Chloropyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((6-Chloropyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (45 mg) and THF (5 mL) To the mixture was added oxalyl chloride (0.10 mL) and DMF (catalytic amount) at room temperature and stirred at room temperature for 1 hour. The reaction mixture was diluted with toluene and then concentrated under reduced pressure. The residue was diluted with THF (5 mL), 28% aqueous ammonia solution (0.50 mL) was added under ice cooling, and the mixture was stirred at 0 ° C for 1 hour and overnight at room temperature. The reaction mixture was added to water and extracted twice with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane). The obtained product was collected by filtration and washed with ethyl acetate / hexane to give the title compound (40 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.93-3.03 (2H, m), 3.20-3.29 (2H, m), 7.54 (2H, s), 7.63 (1 H, dd, J = 8.8, 0.5 Hz ), 7.87 (1 H, dd, J = 8.8, 3.1 Hz), 8.51 (1 H, s), 8.52 (1 H, dd, J = 3.1, 0.5 Hz).

Example 11
8-((6-Cyanopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((6-Chloropyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (150 mg) and DMA (5 mL) Zinc cyanide (37 mg), DPPF (48 mg), zinc (6 mg) and Pd ₂ (dba) ₃ (39 mg) were added to the mixture at room temperature, and then stirred at 100 ° C for 4 hours under a nitrogen atmosphere. did. The reaction mixture was diluted with ethyl acetate and water, and the insolubles were filtered off through celite. The filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and saturated brine solution and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate). The obtained product was collected by filtration and washed with ethyl acetate / hexane to give the title compound (124 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.94-3.04 (2H, m), 3.21-3.30 (2H, m), 7.61 (2H, s), 7.89 (1 H, dd, J = 8.7, 2.9 Hz ), 8.13 (1 H, dd, J = 8.7, 0.6 Hz), 8.51 (1 H, s), 8.82 (1 H, dd, J = 2.9, 0.5 Hz).

Example 12
5-((6-Carbamoyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazol-8-yl) oxy) pyridine-2-carboxylic acid
8-((6-Cyanopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (80 mg), 20% sodium ethoxide / A mixture of ethanol solution (388 mg), ethanol (2 mL) and THF (2 mL) was stirred at room temperature for 5 days. To the reaction mixture was added 6 N aqueous hydrochloric acid (2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was basified with saturated aqueous sodium bicarbonate solution. The solvent was evaporated under reduced pressure and then diluted with water. The precipitate was collected by filtration, washed with water and purified by silica gel column chromatography (methanol / ethyl acetate). To a mixture of the obtained product and THF (3 mL) / ethanol (3 mL) was added 2 N aqueous sodium hydroxide solution (0.5 mL) at room temperature, and the mixture was stirred at room temperature for 5 minutes. Water (2 mL) was added to the reaction mixture, and stirred at room temperature for 2 hours. To the reaction mixture was added 2 N aqueous hydrochloric acid (0.5 mL). The reaction mixture was diluted with water, the precipitate was collected by filtration, and washed with water and THF to give the title compound (17 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.95-3.04 (2 H, m), 3.26 (2 H, t, J = 7.4 Hz), 7.58 (2 H, s), 7. 80 ( ¹ H, dd, J = 8.7) , 2.9 Hz), 8.11 (1 H, d, J = 8.9 Hz), 8.51 (1 H, s), 8. 73 (1 H, d, J = 2.6 Hz), 13.28 (1 H, brs).

Example 13
8-((6-Carbamoylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) 8-((6-Carbamoylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((6-Cyanopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (70 mg) and DMSO (1 mL) To the mixture were added potassium carbonate (28 mg) and 30% aqueous hydrogen peroxide solution (0.10 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 mL), and the precipitate was collected by filtration and washed with water to give the title compound (68 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.94-3.04 (2H, m), 3.21-3.31 (2H, m), 7.57 (2H, s), 7.67 (1H, brs), 7.83 (1H, dd , J = 8.7, 2.9 Hz), 8.06-8.14 (2H, m), 8.51 (1 H, s), 8.67 (1 H, dd, J = 2.8, 0.5 Hz).

(B) 8-((6-Carbamoylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
5-((6-Carbamoyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazol-8-yl) oxy) pyridine-2-carboxylic acid (200 mg), WSCD (159 mg) A mixture of HOBt (110 mg) and DMF (5 mL) was stirred at room temperature for 1.5 hours. To the reaction mixture was added 28% aqueous ammonia (0.20 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was diluted with aqueous sodium bicarbonate solution, the precipitate was collected by filtration and washed with water. The obtained product was purified by silica gel column chromatography (methanol / ethyl acetate) and washed with water to give the title compound (148 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.93-3.04 (2H, m), 3.21-3.30 (2H, m), 7.58 (2H, s), 7.68 (1H, brs), 7.83 (1H, dd , J = 8.7, 2.8 Hz), 8.06-8.15 (2 H, m), 8.51 (1 H, s), 8. 68 (1 H, dd, J = 2.9, 0.5 Hz).

Example 14
8-((6-Carhamuimidoylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide Example 15
Ethyl 5-((6-Carbamoyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazol-8-yl) oxy) pyridine-2-carboxylate
(A) Ethyl 8-((6-cyanopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate Ethyl 8- ((6 -Chloropyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (150 mg) in mixture with DMA (5 mL), cyanide Zinc fluoride (34 mg), DPPF (42 mg), zinc (5 mg) and Pd ₂ (dba) ₃ (35 mg) were added at room temperature, and then stirred at 100 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and water, and the insolubles were filtered off through celite. The filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (156 mg).
MS: [M + H] ^< +> 383.9.

(B) 8-((6-carbamimidoylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (Example 14) And ethyl 5-((6-carbamoyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazol-8-yl) oxy) pyridine-2-carboxylate (Example 15)
Ethyl 8-((6-Cyanopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (148 mg) in THF (2 mL) 2N aqueous solution of sodium hydroxide (1 mL) was added to a mixture of) / ethanol (2 mL) at room temperature, and stirred at room temperature for 3 hours. To the reaction mixture was added 2 N aqueous hydrochloric acid (1 mL). The solvent was evaporated under reduced pressure, and the residue was diluted with water, the precipitate was collected by filtration and washed with water. A mixture of the obtained product and WSCD (148 mg), HOBt (104 mg) and DMF (2 mL) was stirred at room temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia solution (0.073 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water (2 mL) was added to the reaction mixture and stirred at room temperature for 3 days. After evaporation of the solvent under reduced pressure, the residue was diluted with water. The precipitate was collected by filtration, washed with water and purified by silica gel column chromatography (NH, methanol / ethyl acetate). The fractions containing the desired product are combined and concentrated under reduced pressure, and the residue is collected by filtration, washed with ethyl acetate, and 8-((6-carbamimidoylpyridin-3-yl) oxy) -4, 5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (16 mg) was obtained.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.94-3.03 (2H, m), 3.22-3.30 (2H, m), 7.06-7.47 (2H, m), 7.54 (2H, s), 7.83 (1H , dd, J = 8.8, 2.8 Hz), 8.22 (1 H, d, J = 8.9 Hz), 8.51 (1 H, s), 8. 65 (1 H, d, J = 2.5 Hz).
Similarly, the fractions containing the desired product are combined and concentrated under reduced pressure, the residue is collected by filtration, washed with ethyl acetate / hexane, and ethyl 5-((6-carbamoyl-4,5-dihydrothieno [3 ,, 4-g] [1,2] benzothiazol-8-yl) oxy) pyridine-2-carboxylate (25 mg) was obtained.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.33 (3 H, t, J = 7.1 Hz), 2.93-3.05 (2 H, m), 3.26 (2 H, t, J = 7.3 Hz), 4.35 (2 H, q, J = 7.1 Hz), 7.59 (2 H, s), 7.81 (1 H, dd, J = 8.7, 2.9 Hz), 8.12 (1 H, d, J = 8.7 Hz), 8.51 (1 H, s), 8.76 ( 1 H, d, J = 2.7 Hz).

Example 16
8-((6-Bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) Ethyl 3-((6-bromopyridin-3-yl) oxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 3- (methylsulfonyl) 6-Bromopyridine-3 in a mixture of -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (38.3 g) and ethyl acetate (300 mL) / toluene (300 mL) After adding -ol (25.0 g) and potassium carbonate (26.4 g) at room temperature, the reaction mixture is stirred at 80 ° C. for 5 hours. The reaction mixture was added to water at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and then recrystallized from ethyl acetate / hexane to give the title compound (33.2 g).
MS: [M + H] ⁺ 395.8.

(A ') Ethyl 3-((6-bromopyridin-3-yl) oxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 3- (methylsulfonyl) 6-Bromopyridine in a mixture of 4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (97.8 g) and ethyl acetate (600 mL) / toluene (600 mL) After addition of 3-ol (61.9 g) and micronized potassium carbonate (67.4 g) at room temperature, the reaction mixture was stirred at 81-83 ° C. for 5 hours. The reaction mixture was cooled to 15 ° C. using an ice-cold water bath, and water (1.0 L) was added dropwise at 15-21 ° C. over 20 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give a crude product. The resulting crude product was dissolved in ethyl acetate (115 mL) at 58-61 ° C. To the resulting solution was added dropwise hexane (465 mL) at the same temperature, and then stirred overnight at room temperature. The precipitate was separated by filtration and washed with hexane to give the title compound (88.0 g).
MS: [M + H] ⁺ 396.1.

(B) Ethyl 8-((6-bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate ice cold DMF (300 After adding tribromide phosphite (15.8 mL) dropwise over 40 minutes to mL), the mixture was stirred at 80 ° C. for 30 minutes. In the reaction mixture, ethyl 3-((6-bromopyridin-3-yl) oxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (20.0 g) and DMF ( After dropwise addition of the mixture of 80 mL), the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ammonium thiocyanate (11.8 g) was added to a mixture of the residue and acetone (150 mL) at room temperature and then stirred at 55 ° C. for 1 hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and then recrystallized from ethyl acetate / hexane to give the title compound (15.0 g).
MS: [M + H] ^< +> 436.8.

(B'-1) Ethyl 4-bromo-5-formyl-3-((6-bromopyridine 3-yl) oxy) -6,7-dihydrobenzo [c] thiophene-1-carboxylate ice cold DMF ( The tribromide phosphite (38.0 mL) was added dropwise to a solution of 37.8 mL) in acetonitrile (500 mL) under nitrogen atmosphere at 2 ° C. for 10 minutes, and then stirred at 20 ° C. for 20 minutes. The reaction mixture was heated to 76 ° C. for 30 minutes. The resulting reaction mixture contained ethyl 3-((6-bromopyridin-3-yl) oxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (48.1 g) After a mixture of acetonitrile and acetonitrile (480 mL) / DMF (48 mL) was added dropwise at 73-78 ° C under nitrogen atmosphere over 40 minutes, the mixture was stirred at the same temperature for 10 minutes. After ice-cooling the reaction mixture, water (480 mL) was added dropwise to the reaction mixture over 20 minutes at 3-7 ° C. A mixture of sodium acetate (30.3 g) and water (480 mL) was added dropwise to the reaction solution over 5 minutes at 3-12 ° C., followed by stirring at room temperature for 1 hour. The precipitate was collected by filtration, washed with water and dried at room temperature under reduced pressure for 3 hours to give the title compound (49.1 g).
MS: [M + H] ^< +> 488.0.

(B'-2) Ethyl 8-((6-bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate Ethyl 4- In a mixture of bromo-5-formyl-3-((6-bromopyridine 3-yl) oxy) -6,7-dihydrobenzo [c] thiophene-1-carboxylate (49.1 g) and acetonitrile (1.0 L), Ammonium thiocyanate (39.1 g) was added at room temperature and then stirred at 55-60 ° C. for 1.5 hours. Saturated aqueous sodium bicarbonate solution (1.0 L) was added dropwise to the reaction mixture at 2-8 ° C. over 20 minutes, and the mixture was stirred at room temperature for 1.5 hours. The precipitate was separated by filtration, and the obtained solid was dissolved in ethyl acetate (1.0 L) at 60 ° C. and purified by silica gel column chromatography (NH, ethyl acetate) to obtain a crude product. The resulting crude product was dissolved in ethyl acetate (900 mL) at 60-63 ° C. To the resulting solution was added dropwise hexane (1.2 L) over 40 minutes, and then stirred at 35-40 ° C. for 2 hours and overnight at room temperature. The resulting mixture was ice cooled and stirred at the same temperature for 2 hours. The precipitate was collected by filtration to give the title compound (37.4 g).
MS: [M + H] ^< +> 436.8.

(C) Ethyl 8-((6-bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate 8-((6- Bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (10.0 g) and THF (100 mL) / methanol (50 mL) To the mixture was added 8 N aqueous sodium hydroxide solution (14.3 mL) at room temperature and stirred at the same temperature for 4 hours. To the reaction mixture were added 6 N aqueous hydrochloric acid (18.5 mL) and saturated aqueous ammonium chloride (150 mL) at room temperature, and the mixture was extracted with a mixture of ethyl acetate / THF. The aqueous layer was extracted with ethyl acetate, the extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to give the title compound (7.39 g).
MS: [M + H] ^< +> 408.8.

(D) 8-((6-bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((6-Bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (1.93 g) and DMF (20 mL) To the mixture was added HOBt (955 mg), WSC (1.25 mL), DIEA (2.50 mL), and ammonium chloride (1.27 g) at room temperature and stirred overnight at the same temperature. The reaction mixture was added to water at room temperature, the precipitate was separated by filtration, and washed with a saturated aqueous sodium bicarbonate solution and water to give the title compound (1.58 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.93-3.04 (2H, m), 3.21-3.29 (2H, m), 7.55 (2H, s), 7.71-7.81 (2H, m), 8.49-8.56 (2H, m).

Example 17
8-((6- (Methylcarbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((6-bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (150 mg), trans-bis (acetato) Bis [o- (di-o-tolylphosphino) benzyl] dipalladium (II) (36 mg), tri (tert-butylphosphonium) tetrafluoroborate (22 mg), hexacarbonylmolybdenum (101 mg), 2.0 M methyl A mixture of amine THF solution (367 μL), DBU (635 μL), and THF (2 mL) was stirred under microwave irradiation at 125 ° C. for 1 hour. The reaction mixture was added to a mixture of ethyl acetate / THF / water. The organic layer was separated, washed with saturated ammonium chloride and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from THF / heptane to give the title compound (70 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.82 (3H, d, J = 4.8 Hz), 2.94-3.04 (2H, m), 3.21-3.30 (2H, m), 7.58 (2H, s), 7.84 (1H, dd, J = 8.7, 2.8 Hz), 8.09 (1 H, dd, J = 8.7, 0.6 Hz), 8.51 (1 H, s), 8.69 (1 H, dd, J = 2.8, 0.6 Hz), 8.75 (1H, q, J = 4.8 Hz).

Example 18
8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) Ethyl 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6- Carboxylate ethyl 8-((6-bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (506 mg), palladium acetate A mixture of (II) (28 mg), DPPF (68 mg), triethylamine (490 μL), 2-methoxyethanamine (154 μL), and DMF (5 mL) under a carbon monoxide atmosphere at 4 atm at 120 ° C. The mixture was stirred for 400 minutes. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, NH, ethyl acetate / hexane) to give the title compound (230 mg).
MS: [M + H] ^< +> 460.0.

(A'-1) Ethyl 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole -6-Carboxylate Ethyl 8-((6-bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (19.7 g) A mixture of bis (triphenylphosphine) palladium (II) dichloride (1.58 g), triethylamine (18.8 mL), 2-methoxyethanamine (7.82 mL), and DMA (440 mL) under a carbon monoxide atmosphere at 1 atm. The mixture was stirred at 80 ° C. for 4.0 hours. The reaction mixture was added to a mixed solution of water (400 mL) / THF (200 mL) at room temperature. The precipitate was filtered off and washed with THF (200 mL), and the filtrate was extracted with ethyl acetate (400 mL). The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (15.6 g).

(A′-2) Ethyl 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole -6-Carboxylate Ethyl 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno obtained by the method of Example 18 (A'-1) To a mixture of [3,4-g] [1,2] benzothiazole-6-carboxylate (25.6 g) and THF (500 mL), NH silica gel (179 g) was added and stirred at room temperature overnight. The NH silica gel was filtered off and washed with ethyl acetate, and the filtrate was evaporated under reduced pressure to give the title compound (25.3 g).
MS: [M + H] ⁺ 46.2.

(B) 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid Ethyl acid 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate To a mixture of (215 mg) and THF (2 mL) / methanol (2 mL) was added 2 N aqueous sodium hydroxide solution (1.17 mL) at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture were added 2 N aqueous hydrochloric acid solution (1.15 mL) and saturated aqueous ammonium chloride solution at room temperature, and the mixture was extracted with a mixture of ethyl acetate / THF. The aqueous layer was extracted with ethyl acetate, the extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (192 mg).
MS: [M + H] ^< +> 432.0.

(B ') 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6- Ethyl carboxylate 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxy The ratate (110 g) was dissolved in THF (900 mL) at 60 ° C., and ethanol (900 mL) was added. After the mixture was cooled to 22 ° C., 2 N aqueous solution of sodium hydroxide (240 mL) was added dropwise over 20 minutes at 26 ° C. or less. The reaction mixture was stirred at room temperature for 2 hours. After ice-cooling the reaction mixture, water (1.8 L) was added dropwise over 40 minutes. After 2 N hydrochloric acid aqueous solution (240 mL) was added dropwise over 30 minutes at 3-4 ° C., the mixture was stirred at the same temperature for 2 hours. The precipitate was collected by filtration, washed with water (2.0 L) and dried at 70 ° C. under reduced pressure for 2 days to give the title compound (100 g).
MS: [M + H] ⁺ 42.2.

(C) 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (182 HOBt (87 mg) and WSCD (138 mg) were added to a mixture of mg) and DMF (5 mL) at room temperature and stirred at the same temperature for 1 hour. A 28% aqueous ammonia solution (264 μL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to saturated aqueous sodium bicarbonate solution at room temperature and extracted with a mixture of ethyl acetate / THF. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) and recrystallized from 5% aqueous ethanol / water to give the title compound (104 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.95-3.04 (2H, m), 3.22-3.31 (5H, m), 3.44-3.53 (4H, m), 7.58 (2H, s), 7.85 (1H , dd, J = 8.7, 2.9 Hz), 8. 10 (1 H, d, J = 8.7 Hz), 8.5 1 (1 H, s), 8.63-8.70 (1 H, m), 8. 71 (1 H, dd, J = 2.9, 0.5) Hz).

(C'-1) 1-Hydroxybenzotriazole ammonium salt
To a mixture of 1-hydroxybenzotriazole monohydrate (153 g) and acetone (1.5 L), a 28% aqueous ammonia solution (60.8 g) was added at room temperature and stirred at the same temperature for 4.0 hours. The precipitate was filtered off and washed with acetone (300 mL) and diethyl ether (500 mL) to give the title compound (145 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.05-7.13 (2H, m), 7.21 (1 H, brs), 7.39-7.49 (1 H, m), 7.59-7.70 (1 H, m).

(C'-2) 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole 6-carboxamide
8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid g) WSCD (80.0 g) was added to a mixture of 1-hydroxybenzotriazole ammonium salt (69.0 g) and DMF (1.4 L) at room temperature and stirred at the same temperature for 1.5 hours. After ice-cooling the reaction mixture, water (2.8 L) was added dropwise over 50 minutes at 10 ° C. or less, and stirred at 2-4 ° C. for 1.5 hours. The precipitate was collected by filtration, washed with water (2.8 L), and dried at 70 ° C. under reduced pressure for 2 days to give the title compound (149 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.94-3.04 (2H, m), 3.22-3.32 (5H, m), 3.44-3.52 (4H, m), 7.58 (2H, s), 7.85 (1H , dd, J = 8.7, 2.6 Hz), 8.11 (1 H, d, J = 8.7 Hz), 8.51 (1 H, s), 8.63-8.70 (1 H, m), 8. 71 (1 H, d, J = 2.6 Hz) .

(C'-3) 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole 6-carboxamide 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3, obtained by the method of Example 18 (C′-2) The solution obtained was dissolved after dissolving 4-g] [1,2] benzothiazole-6-carboxamide (380 g) in a mixture of DMSO (1140 mL) / ethanol (1140 mL) at 60 ° C. . Water (4560 mL) was added dropwise to the filtrate at 60-62 ° C. over 2.0 hours, and the mixture was stirred at the same temperature for 1 hour. Water (2280 mL) was added dropwise to the mixture at 57-60 ° C. over 1.5 hours, then the mixture was cooled to 25 ° C. and stirred for 5 hours. The precipitate was collected by filtration, washed with water (7.5 L) and dried at 60 ° C. under reduced pressure for 2 days to give the title compound (374 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.94-3.05 (2H, m), 3.22-3.32 (5H, m), 3.44-3.52 (4H, m), 7.58 (2H, s), 7.85 ( 1H, dd, J = 8.7, 3.0 Hz), 8.11 (1 H, d, J = 8.7 Hz), 8.51 (1 H, s), 8.63-8.70 (1 H, m), 8.71 (1 H, d, J = 3.0 Hz) ).

(D) 8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((6-bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (150 mg), trans-bis (acetato) Bis [o- (di-o-tolylphosphino) benzyl] dipalladium (II) (36 mg), tri (tert-butylphosphonium) tetrafluoroborate (22 mg), hexacarbonyl molybdenum (101 mg), 2-methoxy A mixture of ethanamine (65 μL), DBU (635 μL), and THF (2 mL) was stirred under microwave irradiation at 125 ° C. for 1 hour. The reaction mixture was added to a mixture of ethyl acetate / THF / water. The organic layer was separated, washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) and recrystallized from ethyl acetate / heptane to give the title compound (47 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.94-3.03 (2H, m), 3.22-3.30 (5H, m), 3.43-3.51 (4H, m), 7.58 (2H, s), 7.85 (1H , dd, J = 8.7, 2.8 Hz), 8.10 (1 H, dd, J = 8.7, 0.5 Hz), 8.51 (1 H, s), 8.63-8.69 (1 H, m), 8.71 (1 H, dd, J = 2.8) , 0.5 Hz).

Example 19
8-((6- (morpholin-4-ylcarbonyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) Methyl 5-((6-carbamoyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazol-8-yl) oxy) pyridine-2-carboxylate
8-((6-Bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (1.57 g), palladium (II) acetate ( A mixture of 192 mg), DPPF (218 mg), triethylamine (1.07 mL) and methanol (20 mL) / DMF (10 mL) was stirred at 70 ° C. under 3 atmospheres pressure for 7 hours under carbon monoxide atmosphere. After adding ethyl acetate / THF and a saturated aqueous sodium bicarbonate solution to the reaction mixture, the organic layer was separated. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (592 mg).
MS: [M + H] ^< +> 387.9.

(B) methyl 5-((6-carbamoyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazol-8-yl) oxy) pyridine-2-carboxylate 5-((6- Carbamoyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazol-8-yl) oxy) pyridine-2-carboxylate (650 mg) and THF (3 mL) / methanol (3 mL) To the mixture was added 2 N aqueous sodium hydroxide solution (4.19 mL) and stirred at room temperature for 2 hours. To the reaction mixture were added 2 N aqueous hydrochloric acid (4.10 mL) and saturated aqueous ammonium chloride (50 mL) at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (516 mg).
MS: [M + H] ^< +> 373.9.

(C) 8-((6- (morpholin-4-ylcarbonyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
5-((6-Carbamoyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazol-8-yl) oxy) pyridine-2-carboxylic acid (100 mg) and DMF (2 mL) To the mixture was added HOBt (54 mg), WSC (71 μL), DIEA (142 μL), and morpholine (36 μL) at room temperature and stirred overnight at the same temperature. The reaction mixture was added to saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) and recrystallized from THF heptane to give the title compound (51 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.94-3.03 (2H, m), 3.21-3.30 (2H, m), 3.43-3.71 (8H, m), 7.56 (2H, s), 7.73 (1H , dd, J = 8.6, 0.5 Hz), 7.86 (1 H, dd, J = 8.6, 2.9 Hz), 8.52 (1 H, s), 8.65 (1 H, dd, J = 2.9, 0.5 Hz).

Example 20
8-(((6-(((3-Methyloxetan-3-yl) carbonyl) amino) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole -6- carboxamide
(A) Ethyl 8-((6-((diphenylmethylene) amino) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate Ethyl 8-((6-bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (3.98 g), 1,1- Diphenylmethanimine (2.28 mL), di-tert-butyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (581 mg), Pd ₂ (dba) ₃ (512 mg), sodium tert- A mixture of butyrate (1.31 g) and toluene (80 mL) was stirred at 60 ° C. for 1 hour under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, insolubles were filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (2.32 g).
MS: [M + H] ⁺ 538.1.

(B) Ethyl 8-((6-aminopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate 8-((6- ((Diphenylmethylene) amino) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (2.30 g) and THF (15 mL) To a mixture of / ethanol (10 mL) was added 2 N aqueous sodium hydroxide solution (5 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added 2 N aqueous hydrochloric acid (5 mL). The solvent was evaporated under reduced pressure, and the residue was diluted with water, the precipitate was collected by filtration and washed with water. To a mixture of the obtained product and THF (30 mL) was added 1 N aqueous hydrochloric acid (2 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour and at 60 ° C. for 1 hour. To the reaction mixture was added 1 N aqueous sodium hydroxide solution (2 mL), and the mixture was diluted with ethyl acetate and water. The precipitate was collected by filtration and washed with ethyl acetate and water to give the title compound (1.17 g).
MS: [M + H] ^< +> 345.9.

(C) 8-((6-Aminopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((6-Aminopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (1.16 g), WSCD (974 mg) A mixture of HOBt (690 mg) and DMF (10 mL) was stirred at room temperature for 30 minutes. Under ice-cooling, 28% aqueous ammonia solution (0.40 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was diluted with aqueous sodium bicarbonate solution. The precipitate was collected by filtration and washed with water to give the title compound (1.16 g).
MS: [M + H] ^< +> 344.9.

(D) 8-(((6-(((3-methyloxetan-3-yl) carbonyl) amino) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2 ] Benzothiazole-6-carboxamide
Oxalyl chloride (61 μL) and DMF (3 μL) were added to a mixture of 3-methyloxetane-3-carboxylic acid (82 mg) and THF (1 mL) under ice-cooling and stirred for 30 minutes under ice-cooling . The obtained reaction mixture was subjected to 8-((6-aminopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (80 mg) The mixture was added to a mixture of 1 and pyridine (1 mL) at room temperature, and stirred at room temperature for 1 hour. The reaction mixture was diluted with water, acidified with 1 N aqueous hydrochloric acid, and extracted twice with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate). The obtained product was collected by filtration and washed with ethyl acetate / hexane to give the title compound (38 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.62 (3H, s), 2.92-3.03 (2H, m), 3.19-3.29 (2H, m), 4.34 (2H, d, J = 6.2 Hz), 4.82 (2H, d, J = 6.2 Hz), 7.48 (2H, s), 7.87 (1 H, dd, J = 9.1, 3.0 Hz), 8.19 (1 H, d, J = 9.2 Hz), 8.45 (1 H, dd , J = 3.0, 0.5 Hz), 8.51 (1 H, s), 10.75 (1 H, s).

Example 21
8-((6-(((1-hydroxycyclopropyl) amino) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-) Carboxamide
(A) 1-Acetoxycyclopropanecarboxylic acid
A mixture of 1-hydroxycyclopropanecarboxylic acid (600 mg) and acetic anhydride (2 mL) was refluxed for 2 hours. The reaction mixture was diluted with water (5 mL) and concentrated under reduced pressure. The residue was diluted with toluene and concentrated under reduced pressure to give the title compound (796 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 1.17-1.36 (2H, m), 1.51-1.70 (2H, m), 2.10 (3H, s), 3.33-6.83 (1H, m).

(B) 8-((6-(((1-hydroxycyclopropyl) amino) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole -6- carboxamide
Oxalyl chloride (83 μL) and DMF (4 μL) were added to a mixture of 1-acetoxycyclopropanecarboxylic acid (136 mg) and THF (1 mL) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. The obtained reaction mixture was subjected to 8-((6-aminopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (100 mg) The mixture was added to a mixture of 1 and pyridine (1 mL) at room temperature, and stirred at room temperature for 1 hour. The reaction mixture was diluted with water, acidified with 1 N aqueous hydrochloric acid, and extracted twice with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate). To a mixture of the obtained product and ethanol (2 mL) was added 2 N aqueous sodium hydroxide solution (0.3 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 2 N aqueous hydrochloric acid (0.3 mL), then added to water, and extracted twice with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate / hexane to give the title compound (79 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.01-1.09 (2H, m), 1.17-1.25 (2H, m), 2.92-3.03 (2H, m), 3.20-3.29 (2H, m), 6.83 (1H, s), 7.48 (2H, s), 7.89 (1H, dd, J = 9.1, 3.0 Hz), 8.15 (1H, dd, J = 9.1, 0.6 Hz), 8.45 (1 H, dd, J = 3.1 , 0.5 Hz), 8.51 (1 H, s), 9. 62 (1 H, s).

Example 22
8-((6-((2-Hydroxy-2-methylpropanoyl) amino) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6 -Carboxamide
(A) 2-Acetoxy-2-methylpropanoic acid
A mixture of 2-hydroxy-2-methylpropanoic acid (3.00 g) and acetic anhydride (6 mL) was refluxed for 2 hours. The reaction mixture was diluted with water (10 mL) and concentrated under reduced pressure. The residue was diluted with toluene and concentrated under reduced pressure to give the title compound (3.93 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 1.58 (6 H, s), 2.07 (3 H, s), 5.69-7.12 (1 H, m).

(B) 8-((6-((2-hydroxy-2-methylpropanoyl) amino) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzo Thiazole-6-carboxamide
Oxalyl chloride (0.19 mL) and DMF (17 μL) were added to a mixture of 2-acetoxy-2-methylpropanoic acid (323 mg) and THF (2 mL) at room temperature and stirred at room temperature for 30 minutes. The obtained reaction mixture (0.50 mL) was added to 8-((6-aminopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide The mixture was added to a mixture of (100 mg) and pyridine (1 mL) at room temperature and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate). To a mixture of the obtained product and ethanol (2 mL) was added 2 N aqueous sodium hydroxide solution (0.3 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 2 N aqueous hydrochloric acid (0.3 mL), and the solvent was evaporated under reduced pressure. The residue was added to water and extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate / hexane to give the title compound (74 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.37 (6H, s), 2.92-3.03 (2H, m), 3.19-3.29 (2H, m), 6.03 (1H, s), 7.48 (2H, s) ), 7.89 (1H, dd, J = 9.1, 3.0 Hz), 8.19 (1 H, dd, J = 9.1, 0.5 Hz), 8.45 (1 H, dd, J = 3.0, 0.5 Hz), 8.51 (1 H, s) , 9.58 (1 H, s).

Example 23
8-((6-Bromo-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) Ethyl 3-((6-bromo-2-methylpyridin-3-yl) oxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 3- (Methylsulfonyl) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (13.2 g) in a mixture of ethyl acetate (100 mL) / toluene (100 mL) 6- After adding bromo-2-methylpyridin-3-ol (9.00 g) and potassium carbonate (9.07 g) at room temperature, the reaction mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was added to water at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (15.9 g).
MS: [M + H] ^< +> 409.8.

(B) Ethyl 8-((6-bromo-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate ice cold After adding tribromide phosphite (12.1 mL) dropwise to DMF (100 mL), the mixture was stirred at 80 ° C. for 30 minutes. The reaction mixture contained ethyl 3-((6-bromo-2-methylpyridin-3-yl) oxy) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (15.9 g) After a mixture of) and DMF (100 mL) was added, the mixture was stirred at 80 ° C for 1 hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ammonium thiocyanate (9.01 g) was added to a mixture of the residue and acetone (150 mL) at room temperature, and the mixture was stirred at 55 ° C. for 1 hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and then recrystallized from ethyl acetate / hexane to give the title compound (8.95 g).
MS: [M + H] ^< +> 450.9.

(C) 8-((6-Bromo-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate ethyl 8- ((6-bromo-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (2.55 g) with THF (20 To a mixture of mL) / methanol (20 mL), 8 N aqueous sodium hydroxide solution (3.53 mL) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture were added 6 N aqueous hydrochloric acid (4.65 mL) and saturated aqueous ammonium chloride (100 mL) at room temperature, and the mixture was extracted with a mixture of ethyl acetate / THF. The aqueous layer was extracted with ethyl acetate, the extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (1.52 g).
MS: [M + H] ^< +> 422.8.

(D) 8-((6-bromo-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((6-Bromo-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (1.52 g) and DMF HOBt (730 mg) and WSCD (1.05 g) were added to the mixture of (15 mL) at room temperature, and stirred at the same temperature for 1 hour. The reaction mixture was ice-cooled, 28% aqueous ammonia solution (2.25 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution, and the precipitate was filtered off and washed with water and diisopropyl ether to give the title compound (932 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.50 (3H, s), 2.94-3.03 (2H, m), 3.20-3.30 (2H, m), 7.51 (2H, s), 7.57 (1H, dd) , J = 8.6, 0.6 Hz), 7.66 (1 H, d, J = 8.6 Hz), 8.52 (1 H, s).

Example 24
8-((6-((2-hydroxy-2-methylpropyl) carbamoyl) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzo Thiazole-6-carboxamide
(A) Ethyl 8-((6-((2-hydroxy-2-methylpropyl) carbamoyl) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1 , 2] Benzothiazole-6-carboxylate Ethyl 8-((6-bromopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxy (996 mg), palladium (II) acetate (28 mg), DPPF (66 mg), triethylamine (935 μL), 1-amino-2-methylpropan-2-ol (320 μL), and DMF (10 mL) The mixture of 2) was stirred at 125 ° C. for 4 minutes at 4 atm under a carbon monoxide atmosphere. The reaction mixture was added to saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate / THF. The extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane, NH, ethyl acetate / hexane) to give the title compound (636 mg).
MS: [M + H] ^< +> 488.0.

(B) 8-((6-((2-hydroxy-2-methylpropyl) carbamoyl) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,1 2] Benzothiazole-6-carboxylic acid ethyl 8-((6-((2-hydroxy-2-methylpropyl) carbamoyl) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3 ,, To a mixture of 4-g] [1,2] benzothiazole-6-carboxylate (632 mg) and THF (3 mL) / methanol (3 mL) was added 2 N aqueous sodium hydroxide solution (3.24 mL) at room temperature The mixture was stirred at the same temperature for 3 hours. To the reaction mixture were added 2 N aqueous hydrochloric acid (3.20 mL) and saturated aqueous ammonium chloride (50 mL) at room temperature, and the mixture was extracted with a mixture of ethyl acetate / THF. The aqueous layer was extracted with ethyl acetate, the extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (687 mg).
MS: [M + H] ^< +> 460.0.

(C) 8-((6-((2-hydroxy-2-methylpropyl) carbamoyl) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,1 2] Benzothiazole-6-carboxamide
8-((6-((2-hydroxy-2-methylpropyl) carbamoyl) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzo HOBt (270 mg) and WSCD (395 mg) were added to a mixture of thiazole-6-carboxylic acid (597 mg) and DMF (10 mL) at room temperature and stirred at the same temperature for 1 hour. To the reaction mixture, 28% aqueous ammonia solution (814 μL) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to saturated aqueous sodium bicarbonate solution at room temperature and extracted with a mixture of ethyl acetate / THF. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) and recrystallized from 5% aqueous ethanol / water to give the title compound (214 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.12 (6H, s), 2.64 (3H, s), 2.96-3.03 (2H, m), 3.23-3.32 (4H, m), 4.73 (1H, s) ), 7.55 (2 H, s), 7.73 (1 H, d, J = 8.5 Hz), 7. 95 (1 H, d, J = 8.4 Hz), 8. 39 (1 H, t, J = 6.1 Hz), 8.52 (1 H, s) ).

(D) 8-((6-((2-hydroxy-2-methylpropyl) carbamoyl) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,1 2] Benzothiazole-6-carboxamide
8-((6-bromo-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (152 mg), trans- Bis (acetato) bis [o- (di-o-tolylphosphino) benzyl] dipalladium (II) (37 mg), tri (tert-butylphosphonium) tetrafluoroborate (23 mg), hexacarbonylmolybdenum (101 mg) A mixture of 1-amino-2-methylpropan-2-ol (70 μL), DBU (621 μL) and THF (2 mL) was stirred under microwave irradiation at 125 ° C. for 1 hour. The reaction mixture was added to a mixture of ethyl acetate / THF / water. The organic layer was separated, washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) and recrystallized from ethyl acetate / heptane to give the title compound (58 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.12 (6H, s), 2.64 (3H, s), 2.95-3.03 (2H, m), 3.21-3.38 (4H, m), 4.72 (1H, s) ), 7.55 (2H, s), 7.73 (1H, d, J = 8.5 Hz), 7.95 (1 H, d, J = 8.5 Hz), 8.38 (1 H, t, J = 6.1 Hz), 8.52 (1 H, s) ).

Example 25
8-((6-((2-methoxyethyl) carbamoyl) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6- Carboxamide
8-((6-bromo-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (154 mg), trans- Bis (acetato) bis [o- (di-o-tolylphosphino) benzyl] dipalladium (II) (37 mg), tri (tert-butylphosphonium) tetrafluoroborate (22 mg), hexacarbonylmolybdenum (104 mg) A mixture of 2-methoxyethanamine (65 μL), DBU (629 μL) and THF (2 mL) was stirred under microwave irradiation at 125 ° C. for 1 hour. The reaction mixture was added to a mixture of ethyl acetate / THF / water. The organic layer was separated, washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate and NH, methanol / ethyl acetate) and recrystallized from ethyl acetate / heptane to give the title compound (31 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.63 (3H, s), 2.95-3.03 (2H, m), 3.28 (5H, s), 3.45-3.52 (4H, m), 7.55 (2H, s) ), 7.72 (1 H, d, J = 8.5 Hz), 7. 93 (1 H, d, J = 8.5 Hz), 8.51 (1 H, s), 8.55-8.67 (1 H, m).

Example 26
8-((6-((Cyclopropylcarbonyl) (methyl) amino) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole 6-carboxamide
(A) Ethyl 8-((6-((cyclopropylcarbonyl) (methyl) amino) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2 ] Benzothiazole-6-carboxylate Ethyl 8-((6-bromo-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6 -Carboxylate (2.5 g) and Pd ₂ (dba) ₃ (0.362 g), sodium tert-butylate (1.065 g), N-methylcyclopropanecarboxamide (2.196 g), X-Phos (0.396 g), and toluene ( After heating the mixture of 35 mL) at 80 ° C. for 2 hours, the reaction mixture was added to water at room temperature and extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.786 g).
MS: [M + H] ⁺ 470.0.

(B) 8-((6-((Cyclopropylcarbonyl) (methyl) amino) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] Benzothiazole-6-carboxamidoethyl 8-((6-((cyclopropylcarbonyl) (methyl) amino) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [ To a mixture of 1,2] benzothiazole-6-carboxylate (785 mg) and THF (6.5 mL) / methanol (6.5 mL) was added 2 N aqueous sodium hydroxide solution (4.2 mL) at room temperature, and then at room temperature Stir for 3.5 hours. To the reaction mixture was added 2 N aqueous hydrochloric acid solution (10 mL) at room temperature, and then extracted twice with ethyl acetate / THF. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. A mixture of the residue and WSCD (481 mg), HOBt (339 mg), and DMF (8 mL) was stirred at room temperature for 2 hours, and then 28% aqueous ammonia solution (1.130 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature overnight and then water was added. The precipitate was separated by filtration to give the title compound (640 mg) as crude crystals. 32 mg of crude crystals were separated by HPLC (C18, mobile phase: water / acetonitrile (system containing 0.1% TFA)), and the obtained fraction was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate / hexane to give the title compound (4.3 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 0.74-0.82 (2H, m), 1.06-1.17 (2H, m), 1.63-1.69 (1H, m), 2.60 (3H, s), 3.06 (2H, t) , J = 7.2 Hz), 3.35 (2 H, t, J = 7.2 Hz), 3. 45 (3 H, s), 5. 59 (2 H, brs), 7.23-7.29 (1 H, m), 7. 49 (1 H, d, J = 8.5 Hz), 8.36 (1 H, s).

Example 27
8-((2-Methyl-6- (methylamino) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide 1 hydrochloride
8-((6-((Cyclopropylcarbonyl) (methyl) amino) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole After adding 2 N aqueous sodium hydroxide solution (3.5 mL) to a mixture of 6-carboxamide (607.5 mg) and THF (4.5 mL) / methanol (4.5 mL) at room temperature, the reaction mixture is heated at 50 ° C for 2 hours, 60 ° C. Stir for 3 hours. The reaction mixture was added to 1 N aqueous sodium hydroxide solution at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and THF (5.0 mL) and 4 N hydrochloric acid / ethyl acetate solution (5.0 mL) were sequentially added to the obtained solid. The precipitate was separated by filtration and washed with ethyl acetate to give the title compound (283 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 1.13 (3 H, d, J = 6.0 Hz), 3.05 (2 H, t, J = 7.4 Hz), 3.36 (2 H, t, J = 7.4 Hz), 3.41 (3 H) , d, J = 2.8 Hz), 4.20 (2 H, s), 5.54 (2 H, brs), 7. 60 (1 H, dd, J = 8.9, 3.0 Hz), 8.36 (1 H, s), 8.41 (1 H, d, J = 3.0 Hz).

Example 28
8-((6- (Acetyl (methyl) amino) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((2-Methyl-6- (methylamino) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide 1 hydrochloride ( After adding acetyl chloride (0.071 mL) to a mixture of 40.7 mg) and pyridine (1.0 mL) at room temperature, the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was added to water at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) and recrystallized from ethyl acetate / hexane to give the title compound (18.0 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 2.14 (3 H, s), 2.58 (3 H, s), 3.05 (2 H, t, J = 7.5 Hz), 3.35 (2 H, t, J = 7.3 Hz), 3.40 (3H, s), 5.56 (2H, brs), 7.18-7.29 (1H, m), 7.49 (1H, d, J = 8.7 Hz), 8.36 (1H, s).

Example 29
8-((6-Amino-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) Ethyl 8-((6-((diphenylmethylene) amino) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole 6-Carboxylate Ethyl 8-((6-bromo-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate ( 2.5 g) and Pd ₂ (dba) ₃ (0.362 g), sodium tert-butylate (0.745 g), di-tert-butyl (2 ′, 4 ′, 6′-triisopropylbiphenyl-2-yl) phosphine (0.353) g) A mixture of 1,1-diphenylmethanimine (1.110 mL), and toluene (19 mL) was stirred at 60 ° C. for 40 minutes. After filtering off the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (1.580 g).
MS: [M + H] ⁺ 552.2

(B) 8-((6-Amino-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide ethyl 8- ( (6-((Diphenylmethylene) amino) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (1580 mg 2N Aqueous sodium hydroxide solution (7.0 mL) was added to a mixture of THF and THF (10 mL) / methanol (10 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3.5 hours. To the reaction mixture were added sequentially 2N aqueous hydrochloric acid solution (9.0 mL) and ethyl acetate / THF at room temperature, and the solid was collected by filtration. A mixture of the obtained solid and WSCD (521 mg), HOBt (367 mg), and DMF (9 mL) was stirred at room temperature for 3 hours, and then 28% aqueous ammonia solution (1.2 mL) was added to the reaction mixture at room temperature . The reaction mixture was stirred at room temperature overnight and then water was added at room temperature. The precipitate was separated by filtration and washed with ethyl acetate / THF to give the title compound (159.7 mg).
¹ H NMR (300 MHz, DMSO) δ 2.18 (3 H, s), 2. 97 (2 H, t, J = 7.7 Hz), 3.23 (2 H, t, J = 7.3 Hz), 6.12 (2 H, s), 6.35 (6 1H, d, J = 8.9 Hz), 7.34 (2H, s), 7.40 (1 H, d, J = 8.7 Hz), 8.49 (1 H, s).

Example 30
8-((6-((Cyclopropylcarbonyl) amino) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((6-Amino-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (532.8 mg) and pyridine ( After adding cyclopropane carbonyl chloride (0.270 mL) to the mixture of 14.0 mL) under ice-cooling, the reaction mixture was stirred at room temperature for 20 minutes. Water is added to the reaction mixture, the precipitate is separated by filtration, and the obtained solid is subjected to silica gel column chromatography (ethyl acetate / hexane) and silica gel column chromatography (NH, ethyl acetate / hexane, methanol / ethyl acetate) After purification, it was recrystallized from ethanol / water. The mixture of the obtained solid and ethyl acetate was stirred at room temperature for 30 minutes, and the solid was collected by filtration to give the title compound (202 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.78-0.86 (4H, m), 1.96-2.07 (1 H, m), 2.41 (3 H, s), 2. 98 (2 H, t, J = 7.2 Hz), 3.23 (2 H, t, J = 7.9 Hz), 7.42 (2 H, brs), 7. 76 (1 H, d, J = 9.0 Hz), 8.00 (1 H, d, J = 8.9 Hz), 8.46-8.54 (1 H, m ), 10.98 (1H, s).

Example 31
8-((6-(((1-hydroxycyclopropyl) amino) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzo) Thiazole-6-carboxamide
Oxalyl chloride (77 μL) and DMF (3 μL) were added to a mixture of 1-acetoxycyclopropanecarboxylic acid (126 mg) and THF (1 mL) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. The resulting reaction mixture was converted to 8-((6-amino-2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide The mixture was added to a mixture of (55 mg) and pyridine (1 mL) at room temperature, and stirred at room temperature for 1 hour. The reaction mixture was diluted with water, acidified with 1 N aqueous hydrochloric acid, and extracted twice with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate). To a mixture of the obtained product and ethanol (2 mL) / THF (2 mL) was added 2 N aqueous sodium hydroxide solution (0.2 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. After adding 2 N hydrochloric acid aqueous solution (0.2 mL) to the reaction mixture, the reaction mixture was added to water and extracted twice with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate / hexane to give the title compound (41 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.01-1.09 (2H, m), 1.16-1.25 (2H, m), 2.42 (3H, s), 2.92-3.04 (2H, m), 3.19-3.29 (2H, m), 6.82 (1 H, s), 7.44 (2 H, s), 7.82 (1 H, d, J = 9.0 Hz), 7.99 (1 H, d, J = 8.8 Hz), 8.51 (1 H, s) , 9.52 (1 H, s).

Example 32
8-((1,3,5-Trimethyl-1H-pyrazol-4-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) Ethyl 4-oxo-3-((1,3,5-trimethyl-1H-pyrazol-4-yl) oxy) -4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Mixture of ethyl 3- (methylsulfonyl) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (1.0 g) and ethyl acetate (5.0 mL) / toluene (5.0 mL) After adding 1,3,5-trimethyl-1H-pyrazol-4-ol (0.459 g) and potassium carbonate (2.297 g) to the solution at room temperature, the reaction mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was added to water at room temperature and then extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.969 g).
MS: [M + H] ^< +> 349.0.

(B) Ethyl 8-((1,3,5-trimethyl-1H-pyrazol-4-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxy After adding tribromide phosphite (0.258 mL) to ice-cold DMF (5.0 mL), the reaction mixture was stirred at 80 ° C. for 25 minutes. Ethyl 4-oxo-3-((1,3,5-trimethyl-1H-pyrazol-4-yl) oxy) -4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate as reaction mixture After a mixture of (476 mg) and DMF (3.0 mL) was added, the mixture was stirred at 80 ° C. for 1 hour. After adding ethyl acetate to the reaction mixture at room temperature, the reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Ammonium thiocyanate (208 mg) was added to a mixture of the residue and acetone (9.0 mL) at room temperature and stirred at 50 ° C. for 2.5 hours. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution at room temperature and extracted twice with a mixture of ethyl acetate / hexane. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (330 mg).
MS: [M + H] ⁺ 390.0.

(C) 8-((1,3,5-Trimethyl-1H-pyrazol-4-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide ethyl 8-((1,3,5-Trimethyl-1H-pyrazol-4-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate (323 mg 2N Aqueous sodium hydroxide solution (2.0 mL) was added to a mixture of THF and THF (3.0 mL) / methanol (3.0 mL) at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. To the reaction mixture was added 2 N aqueous hydrochloric acid (5.0 mL) at room temperature, and the mixture was extracted with ethyl acetate / THF. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. After a mixture of the residue and WSCD (239 mg), HOBt (168 mg), and DMF (5.0 mL) was stirred at room temperature for 40 minutes, 28% aqueous ammonia solution (0.561 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then the reaction mixture was added to water. The precipitate was separated by filtration and recrystallized from ethyl acetate / hexane to give the title compound (181 mg).
¹ H NMR (300 MHz, DMSO) δ 2.04 (3 H, s), 2.16 (3 H, s), 2. 96 (2 H, t, J = 7.3 Hz), 3.20 (2 H, dd, J = 7.5, 6.8 Hz), 3.69 (3H, s), 7.36 (2H, s), 8.49 (1 H, s).

Example 33
8-((6-Oxo-1,6-dihydropyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((6-Chloropyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (100 mg), sodium acetate (113 mg) And a mixture of acetic acid (2 mL) was stirred at 200 ° C. for 2 hours under microwave irradiation. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and water, and then purified by silica gel column chromatography (methanol / ethyl acetate). The fractions containing the desired product were combined and concentrated under reduced pressure, and the residue was partitioned between THF and saturated brine solution. The organic layer was separated and concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate and water to give the title compound (3.2 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.90-3.00 (2H, m), 3.17-3.27 (2H, m), 6.47 (1H, d, J = 9.6 Hz), 7.41 (2H, s), 7.63 (1H, dd, J = 9.7, 3.2 Hz), 7.74-7.89 (1H, m), 8.49 (1H, s), 11.70 (1H, brs).

Example 34
N-Methoxy-N-methyl-8-((2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (83 mg) and DMA (1 mL) To the mixture was added DMAP (88 mg), WSC (64 μL), and N, O-dimethylhydroxyamine 1 hydrochloride (70 mg) at room temperature and stirred at 40 ° C. for 14 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, and silica gel, ethyl acetate) to give the title compound (56 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 2.64 (3 H, s), 3.00 (2 H, t, J = 7.4 Hz), 3.32 (3 H, s), 3. 49 (2 H, t, J = 7.4 Hz), 3.67 (3H, s), 7.17 (1 H, dd, J = 8.3, 4.8 Hz), 7.43 (1 H, dd, J = 8.2, 1.1 Hz), 8.34 (1 H, s), 8.41 (1 H, dd, J = 4.8) , 1.3 Hz).

Example 35
N-tert-Butyl-8-((2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (17.0 mg), tert-butylamine (8.8) A suspension of mg), HATU (29.0 mg) and diisopropylethylamine (0.013 mL) in DMF (1.0 mL) was stirred at room temperature for 1.5 hours. Ethyl acetate and water were added to the reaction mixture and stirred, then the organic layer was extracted and evaporated by an air blowing device. The residue was purified by HPLC (C18, mobile phase: acetonitrile / 10 mM aqueous ammonium bicarbonate) and the solvent was evaporated by an air blowing device to give the title compound (13.3 mg).

Example 36
8-((2-Methylpyridin-3-yl) oxy) -N-phenyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (17.0 mg), aniline (11.2 mg) A suspension of HATU (29.0 mg) and diisopropylethylamine (0.013 mL) in DMF (1.0 mL) was stirred at 70 ° C. for 1.5 hours. Ethyl acetate and water were added to the reaction mixture and stirred, then the organic layer was extracted and evaporated by an air blowing device. The residue was purified by HPLC (C18, mobile phase: acetonitrile / 10 mM aqueous ammonium bicarbonate), and the solvent was evaporated by air spraying to give the title compound (25.3 mg).

Example 37
8-((2-Methylpyridin-3-yl) oxy) -N- (1,3-oxazol-2-yl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole- 6-carboxamide
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (17.0 mg), oxazol-2-amine A suspension of (10.1 mg), HATU (29.0 mg) and diisopropylethylamine (0.013 mL) in DMF (1.0 mL) was stirred at 70 ° C. for 1.5 hours. Ethyl acetate and water were added to the reaction mixture and stirred, then the organic layer was extracted and evaporated by an air blowing device. The residue was purified by HPLC (C18, mobile phase: acetonitrile / 10 mM aqueous ammonium bicarbonate) and the solvent was evaporated by an air sparge device. The residue is purified again by HPLC (C18, mobile phase: water / acetonitrile (system containing 0.1% TFA)), and the solution is filtered using StratoSpheres SPE (PL-HCO3 MP-Resin) and desalted. The solvent was evaporated by an air blowing device to give the title compound (3.2 mg).

Example 38
N-hydroxy-8-((2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (206 mg), hydroxylamine 1 hydrochloride In a mixture of (68 mg), 4-methylmorpholine (72 μL), DMAP (9.7 mg), and DMF (3 mL), 2,4,6-trichloro-1,3,5-triazine (35 mg) It was added at room temperature and stirred at the same temperature for 4 hours. After ice-cooling the reaction mixture, hydroxylamine 1 hydrochloride (82 mg), 4-methylmorpholine (72 μL), and 2,4,6-trichloro-1,3,5-triazine (45 mg) were added, Stir at room temperature for 2 hours. The reaction mixture was ice-cooled, and then hydroxylamine 1 hydrochloride (253 mg), 4-methylmorpholine (40 μL) and 2,4,6-trichloro-1,3,5-triazine (106 mg) were added over 1 hour. And stirred at room temperature for 24 hours. After adding HATU (337 mg) to the reaction mixture and stirring for 19 hours at room temperature and 31 hours at 80 ° C., hydroxylamine 1 hydrochloride (636 mg) was added and stirred for 13 days at 80 ° C. and 4 days at room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is separated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% ammonium carbonate)), the obtained fraction is concentrated under reduced pressure, and the residue is washed with ethyl acetate to give the title compound ( 5.7 mg) was obtained.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.90-3.02 (2H, m), 3.11-3.25 (2H, m, J = 10.9 Hz), 7.34 (1 H, dd, J = 8.3, 4.7 Hz), 7.67 (1 H, d, J = 8.1 Hz), 8. 40 (1 H, d, J = 3.8 Hz), 8. 50 (1 H, s), 9. 17 (1 H, brs), 10. 74 (1 H, brs).

Example 39
1- (8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazol-6-yl) ethanone
N-Methoxy-N-methyl-8-((2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (50 mg) A solution of 3 M methylmagnesium bromide / ether (0.5 mL) was added to a mixture of THF and THF (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours and at 50 ° C. for 12 hours. A 1 M methylmagnesium bromide / THF solution (0.5 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture were added 1 N aqueous hydrochloric acid solution (1 mL) and saturated aqueous sodium bicarbonate solution (20 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / hexane to give the title compound (12 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 2.45 (3H, s), 2.61 (3H, s), 2.89-3.15 (2H, m), 3.29-3.58 (2H, m), 7.12-7. 32 (1H, m) ), 7.51 (1 H, d, J = 8.2 Hz), 8.36 (1 H, s), 8. 48 (1 H, d, J = 4.7 Hz).

Example 40
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carbonitrile
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (82 mg), and THF (2 mL) Pyridine (97 μL) and TFAA (102 μL) were added to the mixture under ice-cooling, and the mixture was stirred for 2 hours under ice-cooling. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and then washed with ethyl acetate / hexane to give the title compound (51 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 2.52-2.69 (3 H, m), 2.94-3.30 (4 H, m), 7. 20-7. 25 (1 H, m), 7. 47 (1 H, dd, J = 8.2, 1.3 Hz ), 8.38 (1 H, s), 8. 48 (1 H, dd, J = 4.8, 1.4 Hz).

Example 41
8- (Methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carboxamide
(A) 2- (1,4-Dioxaspiro [4.5] deca-8-ylidene) hydrazinecarboxamide
Hydrazinecarboxamide 1 hydrochloride (150 g) is added to a mixture of 1,4-dioxaspiro [4.5] decan-8-one (139 g), sodium acetate (146 g) and methanol (2.5 L) at room temperature, and the same temperature is added. Stir overnight. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the precipitate was separated by filtration to give the title compound (158 g).
MS: [M + H] ^< +> 214.0.

(B) 4,7-Dihydro-1,2,3-benzothiadiazole-6 (5H) -one Thionyl dichloride (300 mL) and DCM (1.5 L) in a mixture of 2- (1,4-dioxaspiro [4.5] ] Dec-8-ylidene) hydrazinecarboxamide (64 g) was added under ice-cooling and stirred at the same temperature for 2 hours. The reaction mixture was quenched with ice (500 g) and extracted three times with ethyl acetate. The extracts were combined, washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (5 g).
MS: [M + H] ⁺ 154.9.

(C) 7- (bis (methylsulfanyl) methylene) -4,7-dihydro-1,2,3-benzothiadiazole-6 (5H) -one potassium carbonate (23.29 g), 4,7-dihydro-1, A mixture of 2,3-benzothiadiazol-6 (5H) -one (13.0 g) and DMF (200 mL) was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0-5 ° C., carbon disulfide (7.64 mL) was added, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added iodomethane (13.2 mL) at the same temperature, and the mixture was stirred overnight while warming to room temperature. To the reaction mixture was added water (200 mL) and extracted three times with DCM. The extracts were combined, washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (5 g).
MS: [M + H] ^< +> 258.9.

(D) Ethyl 8- (methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carboxylate
7- (Bis (methylsulfanyl) methylene) -4,7-dihydro-1,2,3-benzothiadiazole-6 (5H) -one (5.0 g), ethyl sulfanyl acetate (2.08 mL), potassium carbonate (2.66) A mixture of g) and ethanol (100 mL) was heated to reflux overnight. The solvent was evaporated under reduced pressure, water (30 mL) was added to the residue, and the precipitate was separated by filtration to give the title compound (3.0 g).
MS: [M + H] ^< +> 313.0.

(E) 8- (Methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carboxylate ethyl 8- (methylsulfanyl) -4,5-dihydrothieno [ 2 N aqueous sodium hydroxide (20 mL) in a mixture of 3,4-g] [1,2,3] benzothiadiazole-6-carboxylate (1.81 g), THF (20 mL) and ethanol (20 mL) Was added at room temperature and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and the pH was adjusted to 3-4. The precipitate was separated by filtration to give the title compound (1.35 g).
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.72 (3 H, s), 3.39-3.46 (4 H, m), 13. 49 (1 H, s).

(F) 8- (Methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carboxamide
8- (Methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carboxylic acid (350 mg), DIEA (477 mg), HATU (702 mg) and The mixture of DMF (15 mL) was stirred at room temperature for 30 minutes. To the reaction mixture, ammonium chloride (200 mg) was added at room temperature and stirred at the same temperature for 3 hours. The reaction mixture was diluted with water (50 mL), and the precipitate was filtered off to give the title compound (300 mg).
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.64 (3H, s), 3.34-3.41 (4H, m), 7.65 (2H, s).

Example 42
8- (Methylsulfonyl) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carboxamide
85% m-CPBA in a mixture of 8- (methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carboxamide (710 mg) and DMF (25 mL) (2 g) was added under ice-cooling, and the mixture was stirred overnight while warming up to room temperature. The reaction mixture is separated by HPLC (C18, mobile phase: water (containing 0.01% TFA) / acetonitrile (containing 0.01% TFA)), and the obtained fraction is concentrated under reduced pressure to give the title compound (360 mg) Obtained.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.35 (2 H, d, J = 7.0 Hz), 3.40-3.43 (5 H, m), 7.95 (1 H, brs). 8.07 (1 H, brs).

Example 43
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carboxamide
A mixture of 2-methylpyridin-3-ol (292 mg), potassium tert-butoxide (326 mg) and DMA (8 mL) was stirred at room temperature for 10 minutes. After adding 8- (methylsulfonyl) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carboxamide (380 mg) to the reaction mixture at room temperature, the temperature is raised to 75 ° C. Warm and stir overnight at the same temperature. The reaction mixture is separated by HPLC (C18, mobile phase: water (containing 0.01% TFA) / acetonitrile (containing 0.01% TFA)), and the obtained fraction is concentrated under reduced pressure to give the title compound (85 mg) Obtained.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.49 (3 H, s), 3.43 (4 H, t, J = 4.0 Hz), 7. 39 (1 H, dd, J = 8.0, 4.5 Hz), 7.52 (2 H, 2 H, brs), 7.77 (1 H, d, J = 8.0 Hz), 8. 45 (1 H, d, J = 4.5 Hz).

Example 44
8- (Methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carbonitrile
Thionyl chloride (0.15) was added to a mixture of 8- (methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carboxamide (90 mg) and DMF (4 mL) mL) was added at room temperature and the reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, and the residue is separated by HPLC (C18, mobile phase: water (containing 0.01% TFA) / acetonitrile (containing 0.01% TFA)), and the obtained fraction is concentrated under reduced pressure. The title compound (52 mg) was obtained.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.65 (3 H, s), 3.26 (2 H, t, J = 7.5 Hz), 3.53 (2 H, t, J = 7.5 Hz).

Example 45
8- (Methylsulfonyl) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carbonitrile
To a mixture of 8- (methylsulfonyl) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carboxamide (120 mg) and DMF (5 mL) was added thionyl chloride (0.2 mL) was added at room temperature and the reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, and the residue is separated by HPLC (C18, mobile phase: water (containing 10 mM ammonium carbonate) / acetonitrile (containing 10 mM ammonium carbonate)), and the obtained fraction is collected under reduced pressure. Concentration gave the title compound (93 mg).
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.22 (3 H, s), 3.29 (2 H, t, J = 7.5 Hz), 3.58 (2 H, t, J = 7.5 Hz).

Example 46
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carbonitrile
8-((2-Methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2,3] benzothiadiazole-6-carboxamide (40 mg) and DMF (5 mL) To the mixture of) thionyl chloride (0.2 mL) was added at room temperature and the reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, and the residue is separated by HPLC (C18, mobile phase: water (containing 0.01% TFA) / acetonitrile (containing 0.01% TFA)), and the obtained fraction is concentrated under reduced pressure. The title compound (9.6 mg) was obtained.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.65 (3 H, s), 3.28 (2 H, t, J = 7.5 Hz), 3.58 (2 H, t, J = 7.5 Hz), 7.33 (1 H, d, J = 4.0 Hz), 7.56 (1 H, d, J = 8.0 Hz), 8.55 (1 H, d, J = 4.0 Hz).

Example 88
8- (Methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
In a mixture of 8- (methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (435 mg) and toluene (10 mL) / THF (10 mL) Oxalyl chloride (0.40 mL), DMF (catalytic amount) were added at room temperature and stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and THF (10 mL) was added to the residue. The reaction mixture was ice-cooled, 28% aqueous ammonia solution (2 mL) was added, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The precipitate was collected by filtration and washed with water to give the title compound (426 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.61 (3H, s), 2.89-2.98 (2H, m), 3.14-3.23 (2H, m), 7.59 (2H, brs), 8.51 (1H, s ).

Example 138
8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide fumaric acid ( 1: 1)
8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (10 g ) Was dissolved in a mixture of THF (200 mL) / methanol (40 mL) at 70 ° C. To the mixture, fumaric acid (5.43 g) was added at the same temperature, cooled to 60 ° C., and stirred at the same temperature for 15 minutes. Heptane (30 mL) was slowly added dropwise to the reaction mixture and stirred at the same temperature for 1 hour. Heptane (30 mL) was slowly added dropwise to the reaction mixture and stirred at the same temperature for 30 minutes. The reaction mixture is cooled to room temperature, stirred at the same temperature for 19 hours, the precipitate is collected by filtration, washed with heptane (90 mL) / 2-butanone (30 mL) to give the title compound (10.84 g) (co-crystal) Got).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.93-3.05 (2H, m), 3.23-3.29 (5H, m), 3.43-3.51 (4H, m), 6.63 (2H, s), 7.56 (2H) , s), 7.85 (1 H, dd, J = 8.7, 2.9 Hz), 8. 10 (1 H, d, J = 8.5 Hz), 8.51 (1 H, s), 8.62-8.72 (2 H, m), 13.12 (2 H, brs).

Example 139
8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide succinic acid 1: 1)
8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (1.5 g ) Was dissolved in a mixture of THF (30 mL) / methanol (6 mL) at 70 ° C. To the mixture was added succinic acid (1.65 g) at the same temperature, cooled to 60 ° C., and stirred at the same temperature for 15 minutes. The reaction mixture was cooled to 50 ° C. and stirred at the same temperature for 1.5 hours. The reaction mixture was cooled to room temperature and stirred at the same temperature for 1.5 hours. Heptane (9 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 16 hours, the precipitate was collected by filtration, washed with heptane (15 mL) / THF (5 mL), The compound (1.75 g) (co-crystal) was obtained.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.42 (4 H, s), 2.92-3.06 (2 H, m), 3.23-3.30 (5 H, m), 3. 47 (4 H, d, J = 2.7 Hz), 7.57 (2H, s), 7.85 (1 H, dd, J = 8.7, 2.9 Hz), 8.10 (1 H, d, J = 8.7 Hz), 8.51 (1 H, s), 8.62-8.68 (1 H, m), 8.71 (1H, d, J = 2.8 Hz), 12.17 (2H, brs).

Example 140
8-Phenoxy-4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
Cesium carbonate (233 mg) in a mixture of 8- (methylsulfonyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (150 mg) and NMP (2 mL) Phenol (0.05 mL) was added at room temperature and then stirred at 140 ° C. for 48 hours. To the reaction mixture were added water (5 mL) and 1 N aqueous hydrochloric acid solution (20 mL) at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (15 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ 3.02 (2 H, t, J = 7.4 Hz), 3.34 (2 H, t, J = 7.2 Hz), 5.46 (2 H, brs), 7.23-7.27 (3 H, m) , 7.41 (2H, t, J = 7.8 Hz), 8.32 (1 H, s).

Working Example 141
8- (Methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid
(A) Ethyl 4-chloro-5-formyl-3- (methylsulfanyl) -6,7-dihydro-2-benzothiophene-1-carboxylate Phosphoric acid trichloride (9.8 mL) in ice-cold DMF (92.4 mL) Was added dropwise and stirred at 80.degree. C. for 30 minutes. To the reaction mixture was added a mixture of ethyl 3- (methylsulfanyl) -4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (9.5 g) and DMF (50 mL) at room temperature After stirring, it was stirred at 80.degree. C. for 1 hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (6.9 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.36 (3 H, t, J = 7.0 Hz), 2.56-2.59 (2 H, m), 2. 67 (3 H, s), 3. 12 (2 H, t, J = 7.3 Hz) , 4.32 (2H, q, J = 7.1 Hz), 10.26 (1H, s).

(B) Ethyl 8- (methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate Ethyl 4-chloro-5-formyl-3- (methylsulfanyl) Ammonium thiocyanate (4.98 g) was added to a mixture of -6,7-dihydro-2-benzothiophene-1-carboxylate (6.9 g) and acetone (50 mL) at room temperature and stirred at 50 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure and then ethyl acetate was added. The obtained organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.5 g).
MS: [M + H] ^< +> 312.

(C) 8- (Methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate ethyl 8- (methylsulfanyl) -4,5-dihydrothieno [3, Potassium trimethylsilanolate (4.3 g) was added to a mixture of 4-g] [1,2] benzothiazole-6-carboxylate (3.5 g) and THF (65 mL) at room temperature and stirred at the same temperature for 16 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.9 g).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.68 (3 H, s), 2. 95 (2 H, t, J = 7.4 Hz), 3. 28 (2 H, t, J = 7.4 Hz), 8.52 (1 H, s) , 13.37 (1H, brs).

Working Example 142
8- (Methylsulfinyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
70% mCPBA (52 mg) in a mixture of 8- (methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (90 mg) and DMF (5 mL) The reaction mixture was added with ice-cooling and stirred at room temperature for 20 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (52 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.96 (2 H, t, J = 7.2 Hz), 3.04 (3 H, s), 3.11-3.25 (2 H, m), 7.81 (1 H, brs), 7.88 ( 1H, brs), 8.58 (1H, s).

Working Example 143
8- (Methylsulfanyl) -N- (1,2-thiazol-3-yl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) 8- (Methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carbonyl chloride
Thionyl chloride (0.46 mL) in a mixture of 8- (methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (300 mg) and toluene (10 mL) Was added and heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, toluene was added to the residue, and concentrated again under reduced pressure to give the title compound (300 mg).

(B) 8- (Methylsulfanyl) -N- (1,2-thiazol-3-yl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
8- (Methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carbonyl chloride (100 mg), 1,2-oxazol-3-amine hydrochloride (68 mg) 1M lithium bis (trimethylsilyl) amide / THF solution (1.3 mL) was added to a mixture of THF and THF (5 mL) at −20 ° C., and the mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (23 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.66 (3 H, s), 2. 97 (2 H, t, J = 7.3 Hz), 3.22 (2 H, t, J = 7.2 Hz), 7. 78 (1 H, d, 7 J = 4.8 Hz), 8.53 (1 H, s), 9.06 (1 H, d, J = 4.7 Hz), 11.38 (1 H, s).

Working Example 146
8- (Methylsulfonyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
70% mCPBA (917 mg) in a mixture of 8- (methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (350 mg) and DMF (10 mL) Was added at room temperature and then stirred at the same temperature for 3 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous sodium thiosulfate solution and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate / hexane (1/1) to give the title compound (368 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.91-3.00 (2H, m), 3.14-3.23 (2H, m), 3.38 (3H, s), 7.94 (2H, brs), 8.59 (1H, s) ).

Working Example 151
8- (Methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carbonitrile
Imidazole (39 mg) in a mixture of 8- (methylsulfanyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (80 mg) and dichloromethane (10 mL), and Pyridine (0.51 mL) was added at room temperature and stirred for 5 minutes at the same temperature. After phosphoric acid trichloride (0.18 mL) was added dropwise to the reaction mixture, the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture under ice-cooling and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (50 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.72 (3 H, s), 3.00-3.09 (4 H, m), 8.56 (1 H, s).

Example 154
8- (Methylsulfinyl) thieno [3,4-g] [1,2] benzothiazole-6-carboxamide
Mixture of 8- (methylsulfinyl) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide (40 mg), manganese dioxide (233 mg) and dichloromethane (15 mL) The tube was sealed and heated to reflux for 3 days. The reaction mixture was filtered using Celite and washed with a mixed solution of THF / methanol (1/1). The filtrate was concentrated under reduced pressure and then washed with hexane to give the title compound (12 mg).
¹ H NMR (400 MHz, DMSO-d ₆ , at 100 ° C.) δ 3.17 (3 H, s), 7.72 (2 H, brs), 7. 94 (1 H, d, J = 9.2 Hz), 8. 27 (1 H, d, J = 9.3 Hz), 9.12 (1 H, s).

Working Example 159
8-ethyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
(A) Ethyl 3-ethyl-4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate Ethyl 3- (methylsulfonyl) -4-oxo-4,5,6,7 To a mixture of 2-tetrahydro-2-benzothiophene-1-carboxylate (1.0 g) and THF (10 mL) was added dropwise a 3 M solution of ethylmagnesium bromide / ether (1.1 mL) under ice-cooling, and then the reaction mixture was added. The mixture was stirred for 16 hours while gradually warming to room temperature. An aqueous citric acid solution was added to the reaction mixture, and concentrated under reduced pressure. To the residue was added water and extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (300 mg).
MS: [M + H] ^< +> 253.

(B) Ethyl 4-bromo-3-ethyl-5-formyl-6,7-dihydro-2-benzothiophene-1-
Carboxylate
The phosphorous tribromide (0.45 mL) was added dropwise to DMF (9.3 mL) under ice-cooling, and the mixture was stirred at 80 ° C for 30 minutes. To the reaction mixture was added a mixture of ethyl 3-ethyl-4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate (400 mg) and DMF (10 mL) at room temperature and heated to 80 ° C. The mixture was stirred for 1 hour. To the reaction mixture was added saturated aqueous sodium carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (500 mg).
MS: [M + H] ^< +> 343.

(C) Ethyl 8-ethyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate Ethyl 4-bromo-3-ethyl-5-formyl-6,7-dihydro Ammonium thiocyanate (332 mg) was added to a mixture of -2-benzothiophene-1-carboxylate (500 mg) and acetone (5 mL) at room temperature, and stirred at 50 ° C. for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture at room temperature and then extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (180 mg).
MS: [M + H] ^< +> 294.

(D) Ethyl 8-ethyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylate 8-ethyl-4,5-dihydrothieno [3,4-g] [1 To a mixture of [2, 2] benzothiazole-6-carboxylate (200 mg) and THF (4 mL) was added potassium trimethylsilanolate (262 mg) at room temperature, and the mixture was stirred at the same temperature for 16 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (150 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.32 (3 H, t, J = 7.3 Hz), 2.89-2.97 (4 H, m), 3. 25 (2 H, t, J = 7.3 Hz), 8.53 (1 H, s).

(E) 8-Ethyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide
HOBt (114 mg), WSCI (163 mg) in a mixture of 8-ethyl-4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxylic acid (150 mg) and DMF (3 mL) mg) was added at room temperature and stirred for 30 minutes at the same temperature. To the reaction mixture, 28% aqueous ammonia solution (0.39 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative TLC (1% methanol / dichloromethane) to give the title compound (46 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.32 (3 H, t, J = 7.4 Hz), 2.87-2.95 (4 H, m), 3.17 (2 H, t, J = 7.1 Hz), 7.49 (2 H, 7 brs), 8.52 (1 H, s).

Examples 47 to 87, 89 to 137, 144, 145, 147 to 150, 152, 153, 155 to 158 and 160 to 167 were produced according to the methods shown in the above examples or the methods analogous thereto.
Example compounds are shown in the following table. MS in the table indicates the measured value.

Formulation example 1
A medicament containing the compound of the present invention as an active ingredient can be produced, for example, by the following formulation.

Granulate after mixing (1), (2), (3) and 1/2 of (4). To this is added the remaining (4) and the whole is enclosed in a gelatin capsule.

Granulate after mixing (1), (2), (3), 2/3 of (4) and 1/2 of (5). The remaining (4) and (5) are added to the granules and pressed into tablets.

Formulation example 2
After dissolving 50 mg of the compound obtained in Example 1 in 50 mL of distilled water for injection, added thereto, distilled water for injection is added to make it 100 mL. The solution is filtered under sterile conditions, then 1 mL aliquots of this solution are taken, filled into injection vials under sterile conditions, lyophilized and sealed.

Test example 1
The CDK8 inhibitory activity and the CDK19 inhibitory activity of the compounds of the present invention were evaluated by the following methods.

The test compound dissolved in DMSO was diluted with assay buffer (25 mM HEPES, 10 mM MgCl ₂ , 2 mM DL-Dithiothreitol, 0.01% Tween-20) to obtain a primary diluted solution with a DMSO concentration of 3%. Dispense 2 μL of the above primary dilution solution into a 384-well plate, and then dilute 267-fold diluted in assay buffer with Eu ³⁺ cryptate conjugated antibody monoclonal antibody anti-glutathione S-transferase (CisBio) and 60 nM Kinase Tracer-236 ( 2 μL of the solution mixed with Life technologies was added. After the above addition, the kinase solution (84 ng / mL CDK8 / CycC (Carna Biosciences) diluted in assay buffer for CDK8 inhibitory activity measurement) and 87 ng / mL CDC2L6 diluted in assay buffer for CDK19 inhibitory activity measurement 2 μL of / CycC (Carna Biosciences) is used respectively. After the addition, the plate was allowed to stand at room temperature for 1 hour, and then the fluorescence intensity (excitation wavelength 320 nm, fluorescence wavelength 615 nm, 665 nm, delay time 50 μsec) was measured with a plate reader EnVision (Perkin Elmer).

The inhibition rate of the test compound to CDK8 or CDK19 can be calculated by the following formula using the fluorescence intensity of the reaction solution under no compound addition condition as the control and the fluorescence intensity of the reaction solution under 10 μM control compound addition condition as a blank.
Inhibition rate (%) = (1− (fluorescence intensity of test compound−blank) ÷ (control−blank)) × 100

As a control compound, commercially available 4- (4- (2,3-dihydro-1,4-benzodioxin-6-yl) -1H-pyrazol-3-yl) benzene-1,3-diol is commercially available. Can be used. The concentrations (IC ₅₀ values) of control compounds required to show 50% inhibition against CDK8 or CDK19 are shown in Table 2 for reference.

  Also, the CDK8 inhibition rate (%) and the CDK19 inhibition rate (%) at 1 μM of the test compound are shown in Table 3.

Test example 2
The human multiple myeloma RPMI 8226 cell growth inhibitory activity of the compound of the present invention was evaluated by the following method.

40 μL (300 cells / well) of cell suspension of human multiple myeloma RPMI 8226 (purchased from Health Protection Agency) was seeded in a 384 well plate and cultured at 37 ° C. in a 5% carbon dioxide incubator for 1 day. After the above culture, each test compound solution was added using TECAN D300 to a test concentration of 1 μM, and culture was further continued for 8 days. After the above culture, 40 μL of CellTiter-GloTM Luminescent Cell Viability Assay reagent (Promega) was added to a 384-well plate, and the luminescence amount was measured with a luminometer. The human multiple myeloma RPMI 8226 cell growth inhibitory activity (inhibition rate (%)) of the test compound was calculated from the following equation, assuming that the amount of ATP remaining reflects the number of cells. In the formula, the 100% control indicates the luminescence of the well to which only 0.1% DMSO is added.
Inhibition rate (%) = (1- (emission amount of test compound) / (100% control)) × 100
The inhibition rate (%) at 1 μM of the test compound is shown in Table 3.

From Table 3, it was shown that the compounds of the present invention strongly inhibit CDK8 and CDK19 and suppress the growth of human multiple myeloma.

Test example 3
The antitumor activity of the compound of the present invention on human colorectal cancer cells SW480 tumor-bearing mice was evaluated by the following method.

Human colorectal cancer cells SW480 were subcutaneously implanted and injected 2.0 × 10 ⁶ each into ⁶ to 7-week-old BALB / c female nude mice (CLEA Japan, Inc.). The tumor diameter of the engrafted tumor was measured 14 days after 7 days after transplantation, and the tumor volume was calculated by the following formula.
Tumor volume = major axis x minor axis x minor axis x (1/2)
Individuals with tumor engraftment with a tumor volume of about 100 mm ³ were selected and 6 animals per group were used for the experiment. A 0.5% methyl cellulose solution (Wako Pure Chemical Industries) suspension of the test compound was orally administered for 14 days at the doses shown in Table 4 (mg / kg, single dose is shown) and the number of doses. The tumor volume was calculated by measuring the tumor diameter on the day before the start of administration and on the day before the end of administration.
The tumor growth rate (T / C (%)) of the test compound administration group compared to the control administration group was calculated by the following formula.
T / C (%) = (tumor volume after completion of administration of test compound administration group-tumor volume on the day before initiation of administration of test compound administration group) / (tumor volume after completion of administration of control administration group-administration of control administration group Tumor volume on the day before start)) × 100
The T / C (%) when each test compound was administered is shown in Table 4.

Table 4 shows that the compounds of the present invention strongly suppress the growth of colorectal cancer cells.

The compounds of the present invention have excellent inhibitory activity against CDK 8/19. Therefore, the compound of the present invention can be used as a CDK8 / 19 inhibitor, and is useful as a preventive or therapeutic agent for CDK8 / 19 related diseases including cancer and the like.
This application is based on Japanese Patent Application Nos. 2014-086924 and 2014-008108 filed in Japan, the contents of which are incorporated in full herein.

Claims (15)

formula:

[In the formula,
R ¹ is
(1) (i) hydroxy group,
(Ii) (a) hydroxy group,
(B) C _1-6 alkoxy group,
(C) cyano group,
(D) optionally halogenated C _3-10 cycloalkyl group,
(E) 5- to 6-membered monocyclic aromatic heterocyclic group,
(F) 3- to 8-membered monocyclic non-aromatic heterocyclic group, and
_{(G) (A) C 1-6} alkyl group, and
_{(B) C 1-6} alkyl - group
An amino group which may be mono- or di-substituted with a substituent selected from
And C _1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(Iii) C _1-6 alkoxy group,
(Iv) optionally halogenated C _3-10 cycloalkyl group,
(V) a C _6-14 aryl group _optionally having 1 to 7 halogen atoms ,
(Vi) a 5- to 6-membered monocyclic aromatic heterocyclic group which may be substituted with 1 to 3 C _1-6 alkyl groups,
(Vii) 3- to 8-membered monocyclic non-aromatic heterocyclic group,
(Viii) C _7-16 aralkyl group, and
(Ix) C _7-16 aralkyloxy group
A carbamoyl group which may be mono- or di-substituted with a substituent selected from
(2) C _1-6 alkyl-carbonyl group,
(3) carboxy group,
(4) _C1-6 alkoxy-carbonyl group, or
(5) Cyano group
And
R ² is a hydrogen atom or
(1) halogen atom,
(2) cyano group,
(3) C _1-6 alkyl group,
(4) (a) hydroxy group, and
(B) _C1-6 alkoxy group
A carbamoyl group optionally mono- or di-substituted with a C _1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(5) C _3-10 cycloalkyl-carbamoyl group,
(6) carboxy group,
(7) C _1-6 alkoxy-carbonyl group,
(8) (a) hydroxy group, and
(B) _C1-6 alkoxy group
And 3 to 14 membered non-aromatic heterocyclic carbonyl group optionally substituted by 1 to 5 substituents selected from
(9) carbamimidoyl group, and
_{(10) (i) C 1-6} alkyl group,
(Ii) (a) hydroxy group, and
(B) _C1-6 alkoxy group
And C _1-6 alkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from
(Iii) a C _3-10 cycloalkyl-carbonyl group which may be substituted by 1 to 3 hydroxy groups,
(Iv) Mono- or di-substituted with a substituent selected from C _1-6 alkoxy-carbonyl group and ( v) oxetanyl-carbonyl group which may be substituted by 1 to 3 C _1-6 alkyl group Amino group which may be
A 5- to 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted by 1 to 3 substituents selected from
R ^3a represents a hydrogen atom or a C _1-6 alkyl group;
R ^4a represents a hydrogen atom;
R ^3b represents a hydrogen atom or a C _1-6 alkyl group;
R ^4b represents a hydrogen atom; or
R ^3b and R ^{4b taken} together (i) form a double bond or (ii) form C ₃ -4 cycloalkyl which may be _optionally substituted with the carbon atom to which they are attached ;
X represents N or CH;
L represents a chain atom group or a bond having a main chain formed of 1 to 3 atoms selected from the group consisting of carbon, oxygen, nitrogen and sulfur . ]
Or a salt thereof. The compound or a salt thereof according to claim 1, wherein R ¹ is a carbamoyl group. The compound or a salt thereof according to claim 1 or 2 , wherein R ^3a , R ^4a , R ^3b and R ^4b are all hydrogen atoms. The compound or its salt of any one of Claims 1-3 whose X is CH. The compound or its salt of any one of Claims 1-4 whose L is -O-. R ² is
( 1) halogen atom,
(2) cyano group,
(3) C _1-6 alkyl group,
(4) (a) a hydroxy group, and (b) a C _1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a C _1-6 alkoxy group; mono- or di-substituted A carbamoyl group which may be
(5) C _3-10 cycloalkyl-carbamoyl group,
(6) carboxy group,
(7) C _1-6 alkoxy-carbonyl group,
(8) (a) a hydroxy group, and (b) a 3- to 14-membered non-aromatic heterocyclic carbonyl group which may be substituted with 1 to 5 substituents selected from C _1-6 alkoxy groups,
(9) carbamimidoyl group, and (10) _{(i) C 1-6} alkyl group,
(Ii) (a) hydroxy group, and
(B) _C1-6 alkoxy group
And C _1-6 alkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from
(Iii) a C _3-10 cycloalkyl-carbonyl group which may be substituted by 1 to 3 hydroxy groups,
_{(Iv) C 1-6} alkoxy - carbonyl group, and (v) 1 to 3 _{C 1-6} alkyl optionally substituted with a group oxetanyl - carbonyl group
A 5- to 6-membered nitrogen-containing aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from an amino group which may be mono- or di-substituted with a substituent selected from ;
R ^3a is a hydrogen atom or a C _1-6 alkyl group;
R ^4a is a hydrogen atom;
R ^3b is a hydrogen atom or a C _1-6 alkyl group, and R ^4b is a hydrogen atom, or R ^3b and R ^4b together form a double bond;
X is N or CH;
The compound according to claim 1 or a salt thereof, wherein L is -O-, -S-, -SO-, -SO ₂ -or a bond.   8-((2-Methyl-1-oxidopyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide, or a salt thereof.   8-((6-((2-methoxyethyl) carbamoyl) pyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide, or salt.   8-((6-((2-hydroxy-2-methylpropyl) carbamoyl) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzo Thiazole-6-carboxamide, or a salt thereof.   8-((6-((Cyclopropylcarbonyl) amino) -2-methylpyridin-3-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide Or its salt.   8-((1,3,5-Trimethyl-1H-pyrazol-4-yl) oxy) -4,5-dihydrothieno [3,4-g] [1,2] benzothiazole-6-carboxamide or a salt thereof . A medicament comprising the compound according to any one of claims 1 to 11 or a salt thereof. The medicament according to claim 12 , which is an inhibitor of CDK8 and / or CDK19. The medicament according to claim 12 , which is a preventive or therapeutic agent for cancer. Use of the compound according to any one of claims 1 to 11 or a salt thereof for producing a preventive / therapeutic agent for cancer.